Novel compositions, uses and methods for making them

ABSTRACT

Generally, the present invention provides novel quinolone compounds and pharmaceutical composition thereof which may inhibit cell proliferation and/or induce cell apoptosis. The present invention also provides methods of preparing such compounds and compositions, and methods of making and using the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 62/128,208, filed Mar. 4, 2015, and which is hereby incorporated byreference in its entirety.

STATEMENT REGARDING FEDERAL FUNDING

This invention was made, in part, with government support under FederalGrant Number W81XWH-15-1-0224 awarded by the Department of DefenseOffice of the Congressionally Directed Medical Research Programs. Thegovernment has certain rights in the invention.

FIELD OF THE INVENTION

The present invention provides novel compounds and pharmaceuticalcomposition thereof which may inhibit cell proliferation and/or inducecell apoptosis. The present invention also provides methods of preparingsuch compounds and compositions, and methods of making and using thesame.

BACKGROUND OF THE INVENTION

Hypertrophy of the nucleolus, the cellular site for ribosome biogenesis,has been linked to malignant transformation for more than a hundredyears. The ribosome is a RNA-protein complex that is responsible for theprotein synthesis (translation) in the cell. Carcinogenesis, with theassociated upregulation of growth and proliferation rates, requires asignificant increase in the rate of translation and hence necessitatesan increase in cellular ribosome content. Ribosome biogenesis is ahighly complex energy-consuming process in which the synthesis ofpre-ribosomal RNA by RNA Polymerase I (Pol I) serves as the ratelimiting step.

Not surprisingly, Pol I transcription in normal cells is tightlycontrolled through the action of multiple tumor suppressor proteins(including p53, pRB and PTEN) which serve as inhibitors. The loss ofsuch control due to mutations in tumor suppressor genes or activation ofcertain oncogenic pathways, such as, cMyc and PI3K/Ak/mTOR, results inthe hyperactivation of Pol I transcription that is commonly found inmalignancy.

In addition to cancer, hyperactivation of Pol I transcription has beenlinked to poor prognosis in multiple sclerosis and has been shown toplay a role in the infections cycle of certain pathologic viruses,including cytomegalovirus, hepatitis B virus and hepatitis C virus.Therefore, agents that selectively disrupt Pol I transcription areconceptually attractive as anticancer, anti-inflammatory and antiviraltherapeutics.

SUMMARY OF THE INVENTION

Provided herein are novel compounds and methods of treating orpreventing any one of diseases or conditions described herein comprisingadministering a therapeutically effective amount of a compound describedherein, or a pharmaceutically acceptable salt, or solvate thereof, to amammal in need thereof. In specific embodiments, the compound inhibitsribosome biogenesis by inhibiting POL1 transcription and the disease orcondition is amenable to treatment or prevention by the inhibition ofPOL1 transcription.

In one aspect, described herein is a method for treating or preventingcancer in a mammal comprising administering a therapeutically effectiveamount of a compound described herein, or a pharmaceutically acceptablesalt, or solvate thereof, to the mammal in need thereof. In anotheraspect, described herein is a method for treating or preventing aninflammatory disease in a mammal comprising administering atherapeutically effective amount of a compound described herein, or apharmaceutically acceptable salt, or solvate thereof, to the mammal inneed thereof.

In still another aspect, described herein is a method for treating orpreventing a proliferative disorder in a mammal comprising administeringa therapeutically effective amount of a compound described herein, or apharmaceutically acceptable salt, or solvate thereof, to the mammal inneed thereof. In another aspect, described herein is a method fortreating or preventing a disease or disorder in a mammal comprisingadministering a therapeutically effective amount of a compound describedherein, wherein the compound inhibits ribosome biogenesis by inhibitingPOL1 transcription.

Other objects, features and advantages of the compounds, methods andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description.

DETAILED DESCRIPTION OF THE INVENTION Compounds

Compounds described herein, including pharmaceutically acceptable salts,prodrugs, active metabolites and pharmaceutically acceptable solvatesthereof, inhibit ribosome biogenesis by inhibiting POL1 transcription.

In one aspect, the present invention provides a compound of Formula I:

and pharmaceutically acceptable salts, esters, prodrugs, hydrates andtautomers thereof; wherein;

each Z₁, Z₂, Z₃, and Z₄ is N, CH, or CR₁, provided any three N arenon-adjacent; and further provided that one or more of Z₁, Z₂, Z₃, andZ₄ is CR₁;

each R₁ is independently an optionally substituted C₁-C₈ alkyl, C₂-C₈heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group, or eachR₁ is independently H, halo, CF₃, OR₂, NR₂R₃, NR₂OR₃, NR₂NR₂R₃, SR₂,SOR₂, SO₂R₂, SO₂NR₂R₃, NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃, NR₂COR₃, CN,COOR₂, COOH, CONR₂R₃, OOCR₂, COR₂, or NO₂;

and wherein R₂ and R₃ groups on the same atom or on adjacent atoms canbe linked to form a 3-8 membered ring, optionally containing one or moreN, O or S atoms; and each R₂ and R₃ groups, and each ring formed bylinking R₂ and R₃ groups together, is optionally substituted with one ormore substituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′,N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN,COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independentlyH, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S;

or each R₁ is independently —W, -L-W, —X-L-A; wherein X is NR₆, O, or S;W is an optionally substituted 4-7 membered azacyclic ring, optionallycontaining an additional heteroatom selected from N, O and S as a ringmember; L is a C₁-C₁₀ alkylene, C₁-C₁₀ heteroalkylene, C₂-C₁₀ alkenyleneor C₂-C₁₀ hetcroalkenylene linker, each of which may be optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, oxo (═O), or C1-C6 alkyl; and A isheterocycloalkyl, heteroaryl or NR₄R₅ where R₄ and R₅ are independentlyH, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl,C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ hetcroalkynyl, C₁-C₈ acyl,C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, orC₆-C₁₂ heteroarylalkyl group,

R₄ and R₅ can be linked to form a 3-8 membered ring, optionallycontaining one or more N, O or S; and each R₄ and R₅ groups, and eachring formed by linking R₄ and R₅ groups together, is optionallysubstituted with one or more substituents selected from halo, ═O, ═N—CN,═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂,NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, whereineach R′ is independently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl,C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, orC₆-C₁₂ heteroarylalkyl, each of which is optionally substituted with oneor more groups selected from halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O; wherein two R′ can belinked to form a 3-7 membered ring optionally containing up to threeheteroatoms selected from N, O and S;

R6 is H, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group,

R₆ can be linked to R₄ or R₅ to form a 3-8 membered ring, and R₄ or R₅is optionally substituted with one or more substituents selected fromhalo, ═O, ═N—CN, ═N—OR′, ═NR—, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂,NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′,COR′, and NO₂, wherein each R′ is independently H, C₁-C₆ alkyl, C₂-C₆heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy,ammo, and ═O; wherein two R′ can be linked to form a 3-7 membered ringoptionally containing up to three heteroatoms selected from N, O and S;

Y is an optionally substituted 5-6 member arbocyclic or heterocyclicring;

X₁ is an optionally substituted C₁-C₈alkyl, C₂-C₈ heteroalkyl, C₂-C₈alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈acyl, C₂-C₈ heteroaryl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group, optionally substituted withone or more halogens, ═O, CF₃, CN, OR₇, NR₈R₉, SR₇, SO₂NR₈R₉, C₁-C₈alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl,C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group; or

X₁ is H, NR₂R₃, SOR₂, SO₂R₂, SO₂NR₂R₃, NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃,NR₂COR₃, CN, COOR₂, ester bioisostere, COOH, carboxy bioisostere,CONR₂R₃, amide bioisostere, OOCR₂, COR₂, or NO₂.

In one aspect, the present invention provides a compound of FormulaII(A), II(B), II(C), II(D) and II(E),

and pharmaceutically acceptable salts, esters, prodrugs, hydrates andtautomers thereof; wherein:

Z₂, Z₃ and Z₄ are independently CH or CR₁;

each R₁ is independently an optionally substituted C₁-C₈ alkyl, C₂-C₈heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl C₆-C₁₀ aryl, C₅-C₁₂heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group, or eachR₁ is independently halo, CF₃, OR₂, NR₂R₃, NR₂OR₃, NR₂NR₂R₃, SR₂, SOR₂,SO₂R₂, SO₂NR₂R₃, NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃, NR₂COR₃, CN, COOR₂,COOH, CONR₂R₃, OOCR₂, COR₂, or NO₂;

or each R₁ is independently —W, -L-W, —X-L-A; wherein X is NR₆, O, or S;W is an optionally substituted 4-7 membered azacyclic ring, optionallycontaining an additional heteroatom selected from N, O and S as a ringmember; L is a C₁-C₁₀, alkylene, C₁-C₁₀ heteroalkylene, C₂-C₁₀alkenylene or C₂-C₁₀ heteroalkenylene linker, each of which may beoptionally substituted with one or more substituents selected from thegroup consisting of halogen, oxo (═O), or C1-C6 alkyl; and Aheterocycloalkyl, heteroaryl or NR₄R₅ where R₄ and R₅ are independentlyH, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl,C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl,C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, orC₆-C₁₂ heteroarylalkyl group;

R₄ and R₅ can be linked to form a 3-8 membered ring, optionallycontaining one or more N, O or S; and, each R₄ and R₅ groups, and eachring formed by linking R₄ and R₅ groups together, is optionallysubstituted with one or more substituents selected from halo, ═O, ═N—CN,═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′,NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, whereineach R′ is independently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl,C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, orC₆-C₁₂ heteroarylalkyl, each of which is optionally substituted with oneor more groups selected from halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O; wherein two R′ can belinked to form a 3-7 membered ring optionally containing up to threeheteroatoms selected from N, O and S;

R₆ is H, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group; or R₆ can be linked to R₄ orR₅ to form a 3-8 membered ring; and R₄ or R₅ is optionally substitutedwith one or more substituents selected from halo, ═O, ═N—CN, ═N—OR′,═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′,NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ isindependently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂heteroarylalkyl, each of which is optionally substituted with one ormore groups selected from halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O; wherein two R′ can belinked to form a 3-7 membered ring optionally containing up to threeheteroatoms selected from N, O and S;

Y is an optionally substituted 5-6 membered carbocyclic or heterocyclicring;

X₁ is an optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group, or X₁ is H, NR₂R₃, SOR₂,SO₂R₂, SO₂NR₂R₃, NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃, NR₂COR₃, CN, COOR₂,COOH, polar substituent, carboxy bioisostere, CONR₂R₃, OOCR₂, COR₂, orNO₂;

wherein R₂ and R₃ groups on the same atom or on adjacent atoms can belinked to form a 3-8 membered ring, optionally containing one or more N,O or S; and each R₂ and R₃ groups, and each ring formed by linking R₂and R₃ groups together, is optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, arylalkyl, or C₆-C₁₂ heteroarylalkyl, each ofwhich is optionally substituted with one or more groups selected fromhalo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S.

In one aspect, the present invention provides a compound of FormulaIII(A), III(B), and III(C):

and pharmaceutically acceptable salts, esters, prodrugs, hydrates andtautomers thereof; wherein:

L is a C₁-C₁₀ alkylene, C₁-C₁₀ heteroalkylene, C₂-C₁₀ alkenylene orC₂-C₁₀ heteroalkenylene linker, each of which may be optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, oxo (═O), or C1-C6 alkyl;

A is heterocycloalkyl, heteroaryl or NR₄R₅ where R₄ and R₅ areindependently H, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl,C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl,C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group.

R₄ and R₅ can be linked to form a 3-8 membered ring, optionallycontaining one or more N, O or S; and each R₄ and R₅ groups, and eachring formed by linking R₄ and R₅ groups together, is optionallysubstituted with one or more substituents selected from halo, ═O, ═N—CN,═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR—CONR′₂,NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, whereineach R′ is independently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl,C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, orC₆-C₁₂ heteroarylalkyl, each of which is optionally substituted with oneor more groups selected from halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O; wherein two R′ can belinked to form a 3-7 membered ring optionally containing up to threeheteroatoms selected from N, O and S;

X is NR₆, O, or S;

R₆ is H, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈acyl C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl,or C₆-C₁₂ heteroarylalkyl group;

R₆ can be linked to R₄ or R₅ to form a 3-8 membered ring; and R₄ or R₅is optionally substituted with one or more substituents selected fromhalo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂,NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′,COR′, and NO₂, wherein each R′ is independently H, C₁-C₆ alkyl, C₂-C₆heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy,amino, and ═O; wherein two R′ can be linked to form a 3-7 membered ringoptionally containing up to three heteroatoms selected from N, O and S;

X1 is an optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group, or X₁ is H, NR₂R₃, SOR₂,SO₂R₂, SO₂NR₂R₃, NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃, NR₂COR₃, CN, COOR₂,ester bioisostere, COOH, carboxy bioisostere, CONR₂R₃, amidebioisostere, OOCR₂, COR₂, or NO₂;

(U)_(n) and (U)_(m) are independently H, halogen, CF₃, CN, OR₇, NR₈R₉,SR₇, SO₂NR₈R₉, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₂-C₁₀ alkenyl, orC₂-C₁₀ heteroalkenyl, each of which may be optionally substituted withone or more halogens ═O, or an optionally substituted 3-7 memberedcarbocyclic or heterocyclic ring;

wherein R₂ and R₃ groups on the same atom r on ad_(j)acent atoms can belinked to form a 3-8 membered ring, optionally containing one or more N,O or S; and each R₂ and R₃ groups, and each ring formed by linking R₂and R₃ groups together, is optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S.

In one aspect, the present invention provides a compound of FormulaIII(A)(1), III(B)(1) and III(C)(1):

and pharmaceutically acceptable salts, esters, prodrugs, hydrates andtautomers thereof; wherein:

L is a C₁-C₁₀ alkylene, C₁-C₁₀ heteroalkylene, C₂-C₁₀ alkenylene orC₂-C₁₀ heteroalkenylene linker, each of which may be optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, oxo (═O), or C1-C6 alkyl;

A is heterocycloalkyl, heteroaryl or NR₄R₅ where R₄ and R₅ areindependently H, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl,C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl,C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group,

R₄ and R₅ can be linked to form a 3-8 membered ring, optionallycontaining one or more N, O or S; and each R₄ and R₅ groups, and eachring formed by linking R₄ and R₅ groups together, is optionallysubstituted with one or more substituents selected from halo, ═O, ═N—CN,═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂, NR′CONR′₂,NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, whereineach R′ is independently. H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl,C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl,C₆-C₁₂ heteroarylalkyl, each of which is optionally substituted with oneor more groups selected from halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O; wherein two R′ can belinked to form a 3-7 membered ring optionally containing up to threeheteroatoms selected from N, O and S;

X is NR₆, O, S;

R₆ is H, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group;

R₆ can be linked to R₄ or R₅ to form a 3-8 membered ring; and R₄ or R₅is optionally substituted with one or more substituents selected fromhalo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂,NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′,COR′, and NO₂, wherein each R′ is independently H, C₁-C₅ alkyl, C₂-C₆heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₅-C₁₀aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy,amino, and ═O; wherein two R′ can be linked to form 3-7 membered ringoptionally containing u tothree heteroatoms selected from N, O and S;

X₂ is an optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C-C;_(8—)al enyl, heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl,C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group;

(U)_(n) and (U)_(m) are independently H. halogen, CF₃, CN, OR₇, NR₈R₉,SR₇, SO₂NR₈R₉, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₂-C₁₀ alkenyl, orC₂-C₁₀ heteroalkenyl, each of which may be optionally substituted withone or more halogens ═O, or an optionally substituted 3-7 memberedcarbocyclic or heterocyclic ring;

wherein R₂ and R₃ groups on the same atom or adjacent atoms can belinked to form a 3-8 membered ring, optionally containing one or more N,O or S; and each R₂ and R₃ groups, and each ring formed by linking R₂and R₃ groups together, is optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H.C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ ) heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ allyl, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl,C₁-C₆ heteroacyl, hydroxy, amino, and ═O; wherein two R′ can be linkedto form a 3-7 membered ring optionally containing up to threeheteroatoms selected from N, O and S.

In some embodiments, L is a bond, C₁-C₁₀ alkylene, heteroalkylene,C₂-C₁₀ alkenylene or C₂-C₁₀ heteroalkenylene linker, each of which isoptionally substituted with one or more substituents selected from thegroup consisting of halogen, oxo (═O), or C₁-C₆ alkyl.

In some embodiments, A is heterocycloalkyl, heteroaryl, quaternary amineor NR₄R₅ where R₄ and R₅ are independently H, optionally substitutedC₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl,C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkylgroup.

In some embodiments, R₄ and R₅ can can be linked to form a 3-8 memberedring, optionally containing one or more N, O or S; and each R₄ and R₅groups, and each ring formed by linking R₄ and R₅ groups together, isoptionally substituted with one or more substituents selected from halo,═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′,NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂; OOCR′, COR′, and NO₂,wherein each R′ is independently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl,C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of which is optionallysubstituted with one or more groups selected from halo, C₁-C₄ alkyl,C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O;wherein two R′ can be linked to form a 3-7 membered ring optionallycontaining up to three heteroatoms selected from N, O and S.

In some embodiments, X is NR₆, O, or S.

In some embodiments, R₆ is H, optionally substituted C₁-C₈ alkyl, C₂-C₈heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group.

In some embodiments, R₆ is linked to R₄ or R₅ to form a 3-8 memberedring; and R₄ or R₅ are optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl,C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂heteroarylalkyl, each of which is optionally substituted with one ormore groups selected from halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O; wherein two R′ can belinked to form a 3-7 membered ring optionally containing up to threeheteroatoms selected from N, O and S.

In some embodiments, X₂ is H, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₂-C₁₀alkenyl, or C₂-C₁₀ heteroalkenyl, each of which is optionallysubstituted with one or more halogens, ═O, or an optionally substituted3-7 membered carbocyclic or heterocyclic ring.

In some embodiments, (U)_(n) and (U)_(m) are independently H, halogen,CF₃, CN, OR₇, NR₈R₉, SR₇, SO₂NR₈R₉, C₁-C₁₀ alkyl, heteroalkyl, C₂-C₁₀alkenyl, or C₂-C₁₀ heteroalkenyl, each of which is optionallysubstituted with one or more halogens, ═O, or an optionally substituted3-7 membered carbocyclic or heterocyclic ring.

In some embodiments, R₂ and R₃ groups on the same atom or on adjacentatoms are linked to form a 3-8 membered ring, optionally containing oneor more N, O or S; and each R₂ and R₃ groups, and each ring formed bylinking R₂ and R₃ groups together, is optionally substituted with one ormore substituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′,N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN,COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independentlyH, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₅ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S.

In some preferred embodiments, X₂ is H.

In one aspect, the present invention provides a compound of FormulaIV(A) and IV(B),

and pharmaceutically acceptable salts, esters, prodrugs, hydrates andtautomers thereof wherein:

B₁ is a bond or C═O, B₂ is X-L-A

L is a C₁-C₁₀ alkylene, C₁-C₁₀ heteroalkylene, C₂-C₁₀ alkenylene orC₂-C₁₀ heteroalkenylene linker, each of which may be optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, oxo (═O), or C₁-C₆ alkyl;

A is heterocycloalkyl, heteroaryl or NR₄R₅ wherein R₄ and R₅ areindependently H, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl,C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl,C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group, or R₄ and R₅ can be linkedto form a 3-8 membered ring, optionally containing one or more N, O orS; and each R₄ and R₅ groups, and each ring formed by linking R₄ and R₅groups together, is optionally substituted with one or more substituentsselected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′,SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂,OOCR′, COR′, and NO₂, wherein each R′ is independently H, C₁-C₆ alkyl,C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy,amino, and ═O; wherein two R′ can be linked to form a 3-7 membered ringoptionally containing up to three heteroatoms selected from N, O and S;

X is CR₆R₆, NR₆, O, or S; wherein R₆ is H, optionally substitutedC₁-C₃alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl,C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group; orR₆ can be linked to R₄ or R₅ to form a 3-8 membered ring;

(U)_(n) and (U)_(m) are independently H, halogen, CF₃, CN, OR₇, NR₈R₉,SR₇, SO₂NR₈R₉, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₂-C₁₀ alkenyl, orC₂-C₁₀ heteroalkenyl, each of which may be optionally substituted withone or more halogens, ═O, or an optionally substituted 3-7 memberedcarbocyclic or heterocyclic ring.

In one aspect, the present invention provides a compound of FormulaV(A), Formula V(B), and Formula V(C):

pharmaceutically acceptable salts, esters, prodrugs, hydrates andtautomers thereof; where:

L is a bond, C₁-C₁₀ alkylene, C₁-C₁₀ heteroalkylene, C₂-C₁₀ alkenyleneor C₂-C₁₀ heteroalkenylene linker, each of which is optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, oxo (═O), or C₁-C₆ alkyl;

A is heterocycloalkyl, heteroaryl or NR₄R₅ where R₄ and R₅ areindependently H, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl,C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl,C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group,

R₄ and R₅ can be linked to form a ^(3.8) membered ring, optionallycontaining one or more N, O or S; and each R₄ and R₅ groups, and eachring formed by linking R₄ and R₅ groups together, is optionallysubstituted with one or more substituents selected from halo, ═O, ═N—CN,═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂,NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, whereineach R′ is independently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl,C₂-C₆ heteroacyl, C₅-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, orC₆-C₁₂ heteroarylalkyl, each of which is optionally substituted with oneor more groups selected from halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O; wherein two R′ can belinked to form a 3-7 membered ring optionally containing up to threeheteroatoms selected from N, O and S;

X is NR₆, O, or S;

R₆ is H, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group;

R₆ can be linked to R₄ or R₅ to form a 3-8 membered ring; and R₄ or R₅is optionally substituted with one or more substituents selected fromhalo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂,NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′,COR′, and NO₂, wherein each R′ is independently H, C₁-C₆ alkyl, C₂-C₆heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy,amino, and ═O; wherein two R′ can be linked to form a 3-7 membered ringoptionally containing up to three heteroatoms selected from N, O and S;

X₂ is H, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀heteroalkenyl, each of which is optionally substituted with one or morehalogens, ═O, or an optionally substituted 3-7 membered carbocyclic orheterocyclic ring;

(U)_(n) and (U)_(m) are independently H, halogen, CF₃, CN, OR₇, NR₈R₉,SR₇, SO₂NR₈R₉, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₂-C₁₀ alkenyl, orC₂-C₁₀ heteroalkenyl, each of which is optionally substituted with oneor more halogens, ═O, or an optionally substituted 3-7 memberedcarbocyclic or heterocyclic ring;

wherein R₂ and R₃ groups on the same atom or on adjacent atoms can belinked to form a 3-8 membered ring, optionally containing one or more N,O or S; and each R₂ and R₃ groups, and each ring formed by linking R₂and R₃ groups together, is optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S.

In one aspect, the present invention provides a compound of FormulaVI(A), VI(B) and VI(C):

and pharmaceutically acceptable salts, esters, prodrugs, hydrates andtautomers thereof; wherein:

B₁ is a bond or C═O;

B₂ is X-L-A

L is a C₁-C₁₀ alkylene, C₁-C₁₀ heteroalkylene, C₂-C₁₀ alkenylene orC₂-C₁₀ heteroalkenylene linker, each of which may be optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, oxo (═O), or C₁-C₆ alkyl;

A is heterocycloalkyl, heteroaryl or NR₄R₅ wherein R₄ and R₅ areindependently H, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl,C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl,C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group, or R₄ and R₅ can be linkedto form a 3-8 membered, ring, optionally containing one or more N, O orS; and each R₄ and R₅ groups, and each ring formed by linking R₄ and R₅groups together, is optionally substituted with one or more substituentsselected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′,SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂,OOCR′, COR′, and NO₂, wherein each R′ is independently H, C₁-C₆ alkyl,C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy,amino, and ═O; wherein two R′ can be linked to form a 3-7 membered ringoptionally containing up to three heteroatoms selected from Ne, O and S;

X is CR₆R₆, NR₆, O, or S; wherein R₆ is H, optionally substituted C₁-C₈alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl,C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group; orR₆ can be linked to R₄ or R₅ to form a 3-8 membered ring;

(U)_(n) and (U)_(m) are independently H, halogen, CF₃, CN, OR₇, NR₈R₉,SR₇, SO₂NR₈R₉, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₂-C₁₀ alkenyl, orC₂-C₁₀ heteroalkenyl, each of which may be optionally substituted withone or more halogens, ═O, or an optionally substituted 3-7 memberedcarbocyclic or heterocyclic ring.

In one aspect, the present invention provides a compound of Formula VII:

and pharmaceutically acceptable salts, esters, prodrugs hydrates andtautomers thereof; wherein:

B is an optionally substituted 5-6 membered carbocyclic or heterocyclicring;

Z₅ is N or CX₂;

each Z₁ and Z₄ is N, CH, or CR₁, provided any three N are non-adjacent;and further provided that one or more of Z₁, Z₂, Z₃, and Z4 is CR₁;

-   each R₁ is independently an optionally substituted C₁-C₈ alkyl,    C₂-C₈ heteroalkyl, C₂-C₈ alkenyl, C₈ heteroalkenyl, C₂-C₈ alkynyl,    C₂-C₈ heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl,    C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl    group, or each R₁ is independently H, halo, CF₃, OR₂, NR₂R₃, NR₂OR₃,    NR₂NR₂R₃, SR₂, SOR₂, SO₂R₂, SO₂NR₂R₃, NR₂SO₂R₃, NR₂CONR₂R₃,    NR₂COOR₃, NR₂COR₃, CN, COOR₂, COOH, CONR₂R₃, OOCR₂, COR₂, or NO₂;

and wherein R₂ and R₃ groups on the same atom or on adjacent atoms canbe linked to form a 3-8 membered ring, optionally containing one or moreN, O or S atoms; and each R₂ and R₃ groups, and each ring formed bylinking R₂ and R₃ groups together, is optionally substituted with one ormore substituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′,N(R′)₂, SR′, SO₂R′, SO₂NR₂, NR═SO₂R′, NR′CONR′₂, NR′CoOR′, NR′COR, CN,COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independentlyH, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S;

Two R1 groups on adjacent atoms may form a carboxylic ring, heterocyclicring, aryl or heteroaryl, each of which may be optionally substitutedand/or fused with a cyclic ring;

or each R₁ is independently —W, -L-W, —X-L-A; wherein X is NR₆, O, or S;W is an optionally substituted 4-7 membered azacyclic ring, optionallycontaining an additional heteroatom selected from N, O and S as a ringmember; L is a C₁-C₁₀ alkylene, C₁-C₁₀ heteroalkylene, C₂-C₁₀ alkenyleneor C₂-C₁₀ heteroalkenylene linker, each of which may be optionallysubstituted with one or snore substituents selected from the groupconsisting of halogen, oxo (═O), or C₁-C₆ alkyl; and A isheterocycloalkyl, heteroaryl or NR₄R₅ where R₄ and R₅ are independentlyH, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl,C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl,C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, orC₆-C₁₂ heteroarylalkyl group,

R₄ and R₅ can be linked to form a 3-8 membered ring, optionallycontaining one or more N, O or S; and each R₄ and R₅ groups, and eachring formed by linking R₄ and R₅ groups together, is optionallysubstituted with one or more substituents selected from halo, ═O, ═N—CN,═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂,NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, whereineach R′ is independently H, C₁-C₆ allyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl,C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, orC₆ -C₁₂ heteroarylalkyl, each of which is optionally substituted withone or more groups selected from halo, C₁-C₄ C₁-C₄ heteroalkyl, C₁-C₆acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O; wherein two R′ can belinked to form a 3-7 membered ring optionally containing up to threeheteroatoms selected from N, O and S;

R₆ is optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group,

R₆ can be linked to R₄ or R₅ to form a 3-8 membered ring; and R₄ or R₅is optionally substituted with one or more substituents selected fromhalo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂,NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′,COR′, and NO₂, wherein each R′ is independently H, C₁-C₆ alkyl, C₂-C₆heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy,amino, and ═O; wherein two R′ can be linked to form a 3-7 membered ringoptionally containing up to three heteroatoms selected from N, O and S;

X1 is an optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group, optionally substituted withone or more halogens, ═O, CF₃, CN, OR₇, NR₈R₉, SR₇, SO₂NR₈R₉, C₁-C₈alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl,C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group,or;

X₁ is H, NR₂R₃, SOR₂, SO₂R₂, SO₂NR₂R₃, NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃,NR₂COR₃, CN, COOR₂, ester bioisostere, COOH, carboxy bioisostere,CONR₂R₃, amide bioisostere, OOCR₂, COR₂, or NO₂;

X₂ is H, halogen, CF₃, CN, OR₇, NR₈R₉, SR₇, SO₂NR₈R₉, C₁-C₁₀ alkyl,C₁-C₁₀ heteroalkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀ heteroalkenyl, each ofwhich may be optionally substituted with one or more halogens, ═O, or anoptionally substituted 3-7 membered carbocyclic or heterocyclic ring.

each X₃, X₄ and X₅ is N or CR₁₀

each R₁₀ is independently an optionally substituted C₁-C₈ alkyl, C₂-C₈heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl C₆-C₁₀ aryl, C₅-C₁₂heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group, or eachR₁ is independently H, halo, CF₃, OR₂, NR₂R₃, NR₂OR₃, NR₂NR₂R₃, SR₂,SOR₂, SO₂R₂, SO₂NR₂R₃, NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃, NR₂COR₃, CN,COOR₂, COOH, CONR₂R₃, OOCR₂, COR₂, or NO₂;

and wherein R₂ and R₃ groups on the same atom or on adjacent atoms canbe linked to form a 3-8 membered ring, optionally containing one or moreN, O or S atoms; and each R₂ and R₃ groups, and each ring formed bylinking R₂ and R₃ groups together, is optionally substituted with one ormore substituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′,N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′CO_(O)R′, NR′COR′,CN, COOR′, _(C)ON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ isindependently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆acyl, C₂-C₆heteroacyl, C₆-C₁₀ aryl, C₅-_(C10) heteroaryl, C₇₋C₁₂ arylalkyl, orC₆-C12 heteroarylalkyl, each of which is optionally substituted with oneor more groups selected from halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁₋C₆acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O; wherein two R′ can belinked to form a 3-7 membered ring optionally containing up to threeheteroatoms selected from N, O and S;

Two R₁₀ groups on adjacent atoms may form a carboxylic ring,heterocyclic ring, aryl or heteroaryl, each of which may be optionallysubstituted and/or fused with a cyclic ring; or each R₁₀ isindependently —W, -L-W, —X-L-A: wherein X is NR₆, O, or S; W is anoptionally substituted 4-7 membered azacyclic ring, optionallycontaining an additional heteroatom selected from N, O and S as a ringmember; L is a C₁-C₁₀ alkylene, C₁-C₁₀ heteroalkylene, C₂-C₁₀ alkenyleneor C₂-C₁₀ heteroalkenylene linker, each of which may be optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, oxo (═O), or C₁-C₆ alkyl; and A isheterocycloalkyl, heteroaryl or NR₄R₅ where R₄ and R₅ are independentlyH, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl,C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl,C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂, heteroaryl, C₇-C₁₂ arylalkyl,C₆-C₁₂ heteroarylalkyl group.

In one aspect, the present invention provides a compound of FormulaVIII:

and pharmaceutically acceptable salts, esters, prodrugs, hydrates andtautomers thereof; wherein:

Z₅ is N or CX₂;

each Z₁ and Z₄ is N, CH, or CR₁;

each R₁ is independently an optionally substituted C₁-C₈ alkyl, C₂-C₈heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group, or eachR₁ is independently H, halo, CF₃, OR₂, NR₂R₃, NR₂OR₃, NR₂NR₂R₃, SR₂,SOR₂, SO₂R₂, SO₂NR₂R₃, NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃, NR₂COR₃, CN,COOR₂, COOH, CONR₂R₃, OOCR₂, COR₂, or NO₂;

and wherein R₂ and R₃ groups on the same atom or on adjacent atoms belinked to form a 3-8 membered ring, optionally containing one or more N,O or S atoms; and each R₂ and R₃ groups, and each ring formed by linkingR₂ and R₃ groups together, is optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C-₁-C₆ acyl, C₂-C₆ heteroa.cyl, C₆-C₁₀aryl,C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ allkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆heteroacyl, hydroxy, amino, and ═O; wherein two R′ can be linked to forma 3-7 membered ring optionally containing up to three heteroatomsselected from N, O and S;

or each R₁ is independently —W, -L-W, —X-L-A; wherein X is NR₆, O, or S;W is an optionally substituted 4-7 membered azacyclic ring, optionallycontaining an additional heteroatom selected from N, O and S as a ringmember; L is a C₁-C₁₀ alkylene, C₁-C₁₀ heteroalkylene, C₂-C₁₀ alkenyleneor C₂-C₁₀ heteroalkenylene linker, each of which may be optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, oxo (═O), or C1-C6 alkyl; and A isheterocycloalkyl, heteroaryl or NR₄R₅ where R₄ and R₅ are independentlyH, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl,C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl,C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, orC₆-C₁₂ heteroarylalkyl group,

R₄ and R₅ can be linked to form a 3-8 membered ring, optionallycontaining one or more N, O or S; and each R₄ and R₅ groups, and eachring formed by linking R₄ and R₅ groups together, is optionallysubstituted with one or more substituents selected from halo, ═O, ═N—CN,═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂,NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, whereineach R′ is independently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl,C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, orC₆-C₁₂ heteroarylalkyl, each of which is optionally substituted with oneor more groups selected from halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O; wherein two R′ can belinked to form a 3-7 membered ring optionally containing up to threeheteroatoms selected from N, O and S;

R₆ is H, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group,

R₆ can be linked to R₄ or R₅ to form a 3-8 membered ring; and R₄ or R₅is optionally substituted with one or more substituents selected fromhalo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂,NR′SO₂R, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′,and NO₂, wherein each R′ is independently H, C₁-C₆ alkyl, C₂-C₆heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy,amino, and ═O; wherein two R′ can be linked to form a 3-7 membered ringoptionally containing up to three heteroatoms selected from N, O and S;

X₁ is an optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group, optionally substituted withone or more halogens, ═O, CF₃, CN, OR₇, NR₈R₉, SR₇, SO₂NR₈R₉, C₁-C₈alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈alkynyl, C₂-C₈ heteroalkynyl, C₁-C₆ acyl, C₂-C₈ heteroacyl, C₁₀ aryl,C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group,or;

X₁ is H, NR₂R₃, SOR₂, SO₂R₂, SO₂NR₂R₃, NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃,NR₂COR₃, CN, COOR₂, ester bioisostere, COOH, carboxy bioisostere,CONR₂R₃, amide bioisostere, OOCR₂, COR₂, or NO₂;

X₂ is H, halogen, CF₃, CN, OR₇, NR₈R₉, SR₇, SO₂NR₈R₉, C₁-C₁₀ alkyl,C₁-C₁₀ heteroalkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀ heteroalkenyl, each ofwhich may be optionally substituted with one or more halogens, ═O, or anoptionally substituted 3-7 membered carbocyclic or heterocyclic ring.

each X₃, X₄ and X₅ is N or CR₁₀

each R₁₀ is independently an optionally substituted C₁-C₈ alkyl, C₂-C₈heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group, or eachR₁ is independently H, halo, CF₃, OR₂, NR₂R₃, NR₂OR₃, NR₂NR₂R₃, SR₂,SOR₂, SO₂R₂, SO₂NR₂R₃, NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃, NR₂COR₃, CN,COOR₂, COOH, CONR₂R₃, OOCR₂, COR₂, or NO₂;

and wherein R₂ and R₃ groups on the same atom or on adjacent atoms canbe linked to form a 3-8 membered ring, optionally containing one or moreN, O or S atoms; and each R₂ and R₃ groups, and each ring formed bylinking R₂ and R₃ groups together, is optionally substituted with one ormore substituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′,N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN,COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independentlyH, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S;

Two R₁₀ groups on adjacent atoms may form a carboxylic ring,heterocyclic ring, aryl or heteroaryl, each of which may be optionallysubstituted and/or fused with a cyclic ring; or each R₁₀ isindependently —W, -L-W, —X-L-A; wherein X is NR₆, O, or S; W is anoptionally substituted 4-7 membered azacyclic ring, optionallycontaining an additional heteroatom selected from N, O and S as a ringmember; L is a C₁-C₁₀ alkylene, C₁-C₁₀ heteroalkylene, C₂-C₁₀ alkenyleneor C₂-C₁₀ heteroalkenylene linker, each of which may be optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, oxo (═O), or C1-C6 alkyl; and A isheterocycloalkyl, heteroaryl or NR₄R₅ where R₄ and R₅ are independentlyH, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl,C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl,C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, orC₆-C₁₂ heteroarylalkyl group,

In one aspect, the present invention provides a compound of FormulaXIV(A), XIV(B), XIV (C) and XIV (D):

and pharmaceutically acceptable salts, esters, prodrugs, hydrates andtautomers thereof; wherein

B₁ is a bond or C═O and B₂ is X-L-A;

L is a C₁-C₁₀ alkylene, C₁-C₁₀ heteroalkylene, C₂-C₁₀ alkenylene orC₂-C₁₀ heteroalkenylene linker, each of which may be optionallysubstituted with one or more substithents selected from the groupconsisting of halogen, oxo (═O), or C₁-C₆ alkyl;

A is heterocycloalkyl, heteroaryl or NR₄R₅ wherein R₄ and R₅ areindependently H, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl,C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl,C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group, or R₄ and R₅ can be linkedto form a 3-8 membered ring, optionally containing one or more N, O orS; and each R₄ and R₅ groups, and each ring formed by linking R₄ and R₅groups together, is optionally substituted with one or more substituentsselected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′,SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂,OOCR′, COR′, and NO₂, wherein each R′ is independently H, C₁-C₆ alkyl,C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy,amino, and ═O; wherein two R′ can be linked to form a 3-7 membered ringoptionally containing up to three heteroatoms selected from N, O and S;

X is CR₆R₆, NR₆, O, or S; wherein R₆ is H, optionally substituted C₁-C₈alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈alkynyl C₂-C₈ heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl,C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group; orR₆ can be linked to R₄ or R₅ to form a 3-8 membered ring;

X₂ is H, halogen, CF₃, CN, OR₇, NR₈R₉, SR₇, SO₂NR₈R₉, C₁-C₁₀ alkyl,C₁-C₁₀ heteroalkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀ heteroalkenyl, each ofwhich may be optionally substituted with one or more halogens, ═O, or anoptionally substituted 3-7 membered carbocyclic or heterocyclic ring.

(U)_(n) and (U)_(m) are independently H, halogen, CF₃, CN, OR₇, NR₈R₉,SR₇, SO₂NR₈R₉, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₂-C₁₀ alkenyl, orC₂-C₁₀ heteroalkenyl, each of which may be optionally substituted withone or more halogens, ═O, or an optionally substituted 3-7 memberedcarbocyclic or heterocyclic ring;

each X₃, X₄ and X₅ is N or CR₁₀;

each R₁₀ is independently an optionally substituted C₁-C₈ alkyl, C₂-C₈heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group, or eachR₁ is independently H, halo, CF₃, OR₂, NR₂R₃, NR₂OR₃, NR₂NR₂R₃, SR₂,SOR₂, SO₂R₂, SO₂NR₂R₃, NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃, NR₂COR₃, CN,COOR₂, COOH, CONR₂R₃, OOCR₂, COR₂, or NO₂;

and wherein a R₂ and R₃ groups on the same atom or on adjacent atoms canbe linked to form a 3-8 membered ring, optionally containing one or moreN, O or S atoms; and each R₂ and R₃ groups, and each ring formed bylinking R₂ and R₃ groups together, is optionally substituted with one ormore substituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′,N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R, NR′CONR′₂, NR′COOR′, NR′COR′, CN,COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independentlyH, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S;

Two R₁₀ groups on adjacent atoms may form a carboxylic ring,heterocyclic ring, aryl or heteroaryl, each of which may be optionallysubstituted and/or fused with a cyclic ring;

or each R₁₀ is independently —W, -L-W, —X-L-A; wherein X is NR₆, O, orS, W is an optionally substituted 4-7 membered azacyclic ring,optionally containing an additional heteroatom selected from N, O and Sas a ring member; L is a C₁-C₁₀ alkylene, C₁-C₁₀ heteroalkylene, C₂-C₁₀alkenylene or C₂-C₁₀ heteroalkenylene linker, each of which may beoptionally substituted with one or more substituents selected from thegroup consisting of halogen, oxo (═O), or C1-C6 alkyl; and A isheterocycloalkyl, heteroaryl or NR₄R₅ where R₄ and R₅ are independentlyH, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl,C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl,C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, orC₆-C₁₂ heteroarylalkyl group.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In one aspect, described herein are pharmaceutical compositionscomprising a compound described herein, or a pharmaceutically acceptablesalt, or solvate thereof, and at least one pharmaceutically acceptableexcipient. In some embodiments, the pharmaceutical composition isformulated for administration to a mammal by intravenous administration,subcutaneous administration, oral administration, inhalation, nasaladministration, dermal administration, or ophthalmic administration. Insome embodiments, the pharmaceutical composition is in the form of atablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion,a solution, an emulsion, an ointment, or a lotion.

In one aspect, described herein is a method of treating or preventingany one of the diseases or conditions described herein comprisingadministering a therapeutically effective amount of a compound describedherein, or a pharmaceutically acceptable salt, or solvate thereof, to amammal in need thereof.

In another aspect, described herein is a method for treating orpreventing cancer, or fibrosis, or combinations thereof in a mammalcomprising administering a therapeutically effective amount of acompound described herein, or a pharmaceutically acceptable salt, orsolvate thereof, to the mammal in need thereof.

In one aspect, described herein is a method for treating or preventingcancer in a mammal comprising administering a therapeutically effectiveamount of a compound described herein, or a pharmaceutically acceptablesalt, or solvate thereof, to the mammal in need thereof. In someembodiments, the cancer is amenable to treatment with an inhibitor ofPOL1 transcription. In some embodiments, the method further comprisesadministering a second therapeutic agent to the mammal in addition tothe compound described herein, or a pharmaceutically acceptable salt, orsolvate thereof.

In one aspect, described herein is a method for treating or preventingan inflammatory disease in a mammal comprising administering atherapeutically effective amount of a compound described herein, or apharmaceutically acceptable salt, or solvate thereof, to the mammal inneed thereof. In some embodiments, the inflammatory disease, is amenableto treatment with an inhibitor of POL1 transcription. In someembodiments, the method further comprises administering a secondtherapeutic agent to the mammal in addition to the compound describedherein, or a pharmaceutically acceptable salt, or solvate thereof.

In one aspect, described herein is a method for treating or preventing aproliferative disorder in a mammal comprising, administering atherapeutically effective amount of a compound described herein, or apharmaceutically acceptable salt, or solvate thereof, to the mammal inneed thereof. In some embodiments, the proliferative disorder isamenable to treatment with an inhibitor of POL1 transcription. In someembodiments, the method further comprises administering a secondtherapeutic agent to the mammal in addition to the compound describedherein, or a pharmaceutically acceptable salt, or solvate thereof.

In one aspect, described herein is a method for treating or preventing adisease or disorder in a mammal comprising administering atherapeutically effective amount of a compound described herein, whereinthe compound inhibits ribosome biogenesis by inhibiting POL1transcription. In some embodiments, the method further comprisesadministering a second therapeutic agent to the mammal in addition tothe compound described herein, or a pharmaceutically acceptable salt, orsolvate thereof.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound described herein, or apharmaceutically acceptable salt thereof, is: (a) systemicallyadministered to the mammal; and/or (b) administered orally to themammal; and/or (c) intravenously administered to the mammal; and/or (d)administered by inhalation; and/or (e) t administered by nasaladministration; or and/or (f) administered by injection to the mammal;and/or (g) administered topically to the mammal; and/or (h) administeredby ophthalmic administration; and/or (i) administered rectally to themammal; and/or (j) administered non-systemically or locally to themammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which the compound is administered oncea day to the mammal or the compound is administered to the mammalmultiple times over the span of one day. In some embodiments, thecompound is administered on a continuous dosing schedule. In someembodiments, the compound is administered on a continuous daily dosingschedule.

In any of the aforementioned aspects involving the treatment of POL1transcription related diseases or conditions are further embodimentscomprising administering at least one additional agent in addition tothe administration of a compound described herein, or a pharmaceuticallyacceptable salt thereof. In various embodiments, each agent isadministered in any order, including simultaneously.

In any of the embodiments disclosed herein, the mammal is a human.

In some embodiments, compounds provided herein are administered to ahuman.

In some embodiments, compounds provided herein are orally administered,

Articles of manufacture, which include packaging material, a compounddescribed herein, or a pharmaceutically acceptable salt thereof, withinthe packaging material, and a label that indicates that the compound orcomposition, or pharmaceutically acceptable salt, tautomers,pharmaceutically acceptable N-oxide, pharmaceutically active metabolite,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate thereof, is used for inhibiting ribosome biogenesis byinhibiting POL1 transcription, or for the treatment, prevention oramelioration of one or more symptoms of a disease or condition thatwould benefit from inhibition of POL1 transcription, are provided.

In one aspect, compounds described herein are in the form ofpharmaceutically acceptable salts. As well, active metabolites of thesecompounds having the same type of activity are included in the scope ofthe present disclosure. In addition, the compounds described herein canexist in unsolvated as well as solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. The solvatedforms of the compounds presented herein are also considered to bedisclosed herein.

“Pharmaceutically acceptable,” as used herein, refers a material, suchas a carrier or diluent, which does not abrogate the biological activityor properties of the compound, and is relatively nontoxic, i.e., thematerial is administered to an individual without causing undesirablebiological effects or interacting in a deleterious manner with any ofthe components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a form of atherapeutically active agent that consists of a cationic form of thetherapeutically active agent in combination with a suitable anion, or inalternative embodiments, an anionic form of the therapeutically activeagent in combination with a suitable cation. Handbook of PharmaceuticalSalts: Properties, Selection and Use. International Union of Pure andApplied Chemistry, Wiley-VCI 2002. S. M. Berge, L. D. Bighley, D. C.Monkhouse, J. Pharm. Sci. 1977, 66, 1-19, P. H. Stahl and C. G. Wermuth,editors, Handbook of Pharmaceutical Salts: Properties, Selection andUse, Weinheim/Zürich: Wiley-VCH/VHCA, 2002. Pharmaceutical saltstypically are more soluble and more rapidly soluble in stomach andintestinal juices than non-ionic species and so are useful in soliddosage forms. Furthermore, because their solubility often is a functionof pH, selective dissolution in one or another part of the digestivetract is possible and this capability can be manipulated as one aspectof delayed and sustained release behaviors. Also, because thesalt-forming molecule can be in equilibrium with a neutral form, passagethrough biological membranes can be adjusted.

In some embodiments, pharmaceutically acceptable salts are obtained byreacting a compound described herein with an acid. In some embodiments,the compound described herein (i.e. free base form) is basic and isreacted with an organic acid or an inorganic acid. Inorganic acidsinclude, but are not limited to, hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid.Organic acids include, but are not limited to, 1-hydroxy-2-naphthoicacid; 2,2-dichioroacetic acid; 2-hydroxyethanesulfonic acid;2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid;acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L);benzenesulfonic acid; benzoic acid; camphoric acid (+);camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid(hexanoir acid); caprylic acid (octanoic acid); carbonic acid; cinnamicacid; citric acid; cyclamic acid; dodecylsulfuric acid;ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaricacid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconicacid (D); glucuronic acid (D); glutamic acid; glutaric acid;glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid;lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid(−L); malonic acid; mandelic acid (DL); methanesulfonic acid;naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinicacid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoricacid; proprionic acid; pyroglutamic acid (−L); salicylic acid; sebacicacid; stearic acid; succinic acid; sulfuric acid; tartaric acid (−L);thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

In some embodiments, a compound described herein is prepared as achloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt,citrate salt or phosphate salt. In some embodiments, a compounddescribed herein is prepared as a hydrochloride salt.

In some embodiments, pharmaceutically acceptable salts are obtained byreacting a compound described herein with a base. In some embodiments,the compound described herein is acidic, and is reacted with a base. Insuch situations, an acidic proton of the compound described herein isreplaced by a metal ion, e.g., lithium, sodium, potassium, magnesium,calcium, or an aluminum ion. In some cases, compounds described hereincoordinate with an organic base, such as, but not limited to,ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine,N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. Inother cases, compounds described herein form salts with amino acids suchas, but not limited to, arginine, lysine, and the like. Acceptableinorganic bases used to form salts with compounds that include an acidicproton, include, but are not limited to, aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,sodium hydroxide, lithium hydroxide, and the like. In some embodiments,the compounds provided herein are prepared as a sodium salt, calciumsalt, potassium salt, magnesium salt, meglumine salt, N-methylglucaminesalt or ammonium salt. In some embodiments, the compounds providedherein are prepared as a sodium salt.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms. In someembodiments, solvates contain either stoichiometric or stoichiometricamounts of a solvent, and are formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Solvates ofcompounds described herein are conveniently prepared or formed duringthe processes described herein. In addition, the compounds providedherein optionally exist in unsolvated as well as solvated forms.

The methods and formulations described herein include the use ofN-oxides (if appropriate), crystalline forms (also known as polymorphs),or pharmaceutically acceptable salts of compounds described herein, aswell as active metabolites of these compounds having the same type ofactivity.

In some embodiments, sites on the organic radicals (e.g. alkyl groups,aromatic rings) of compounds described herein are susceptible to variousmetabolic reactions. Incorporation of appropriate substituents on theorganic radicals will reduce, minimize or eliminate this metabolicpathway. In specific embodiments, the appropriate substituent todecrease or eliminate the susceptibility of the aromatic ring tometabolic reactions is, by way of example only, a halogen, deuterium, analkyl group, a haloalkyl group, or a deuteroalkyl group.

In another embodiment, the compounds described herein are labeledisotopically (e.g. with a radioisotope) or by another other means,including, but not limited to, the use of chromophores or fluorescentmoieties, bioluminescent labels, or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulae and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, forexample, ³H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl. In one aspect,isotopically-labeled compounds described herein, for example those intowhich radioactive isotopes such as ³H and ¹⁴C are incorporated, areuseful in drug and/or substrate tissue distribution assays. In oneaspect, substitution with isotopes such as deuterium affords certaintherapeutic advantages resulting from greater metabolic stability, suchas, for example, increased in vivo half-life or reduced dosagerequirements.

In some embodiments, the compounds described herein possess one or morestereocenters and each stereocenter exists independently in either the Ror S configuration. The compounds presented herein include alldiastereomeric, enantiomeric, atropisomers, and epimeric forms as wellas the appropriate mixtures thereof. The compounds and methods providedherein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z)isomers as well as the appropriate mixtures thereof.

Individual stereoisomers are obtained, if desired, by methods such as,stereoselective synthesis and/or the separation of stereoisomers bychiral chromatographic columns. In certain embodiments, compoundsdescribed herein are prepared as their individual stereoisomers byreacting a racemic mixture of the compound with an optically activeresolving agent to form a pair of diastereoisomeric compounds/salts,separating the diastereomers and recovering the optically pureenantiomers. In some embodiments, resolution of enantiomers is carriedout using covalent diastereomeric derivatives of the compounds describedherein. In another embodiment, diastereomers are separated byseparation/resolution techniques based upon differences in solubility.In other embodiments, separation of steroisomers is performed bychromatography or by the forming diastereomeric salts and separation byrecrystallization, or chromatography, or any combination thereof. JeanJacques, Andre Collet, Samuel H, Wilen, “Enantiomers, Racemates andResolutions”, John Wiley And Sons, Inc., 1981. In some embodiments,stereoisomers are obtained by stereoselective synthesis.

In some embodiments, compounds described herein are prepared as p drugs.A “prodrug” refers to an agent that is converted into the parent drug invivo. Prodrugs are often useful because, in some situations, they areeasier to administer than the parent drug. They are, for instance,bioavailable by oral administration whereas the parent is not. Furtheror alternatively, the prodrug also has improved solubility inpharmaceutical compositions over the parent drug. In some embodiments,the design of a prodrug increases the effective water solubility. Anexample, without limitation, of a prodrug is a compound describedherein, which is administered as an ester (the “prodrug”) but then ismetabolically hydrolyzed to provide the active entity. A further exampleof a prodrug is a short peptide (polyaminoacid) bonded to an acid groupwhere the peptide is metabolized to reveal the active moiety. In certainembodiments, upon in vivo administration, a prodrug is chemicallyconverted to the biologically, pharmaceutically or therapeuticallyactive form of the compound. In certain embodiments, a prodrug isenzymatically metabolized by one or more steps or processes to thebiologically, pharmaceutically or therapeutically active form of thecompound.

Prodrugs of the compounds described herein include, but are not limitedto, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives,N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines,N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters,and sulfonate esters. For example, see Design of Prodrugs, Bundgaard, A.Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.;Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. “Design andApplication of Prodrugs” in A Textbook of Drug Design and Development,Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; andBundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each ofwhich is incorporated herein by reference.

In some embodiments, a hydroxyl group in the compounds disclosed hereinis used to form a prodrug, wherein the hydroxyl group is incorporatedinto an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester,aryl ester, phosphate ester, sugar ester, ether, and the like. In someembodiments, a hydroxyl group in the compounds disclosed herein is aprodrug wherein the hydroxyl is then metabolized in vivo to provide acarboxylic acid group. In some embodiments, a carboxyl group is used toprovide an ester or amide (i.e. the prodrug), which is then metabolizedin vivo to provide a carboxylic acid group. In some embodiments,compounds described herein are prepared as alkyl ester prodrugs.

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a compound described herein as set forthherein are included within the scope of the claims. In some cases, someof the herein-described compounds are a prodrug for another derivativeor active compound.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferasescatalyze the transfer of an activated glucuronic-acid molecule toaromatic alcohols, aliphatic alcohols, carboxylic acids, amines and freesulphydryl groups. Metabolites of the compounds disclosed herein areoptionally identified either by administration of compounds to a hostand analysis of tissue samples from the host, or by incubation ofcompounds with hepatic cells in vitro and analysis of the resultingcompounds,

Synthesis of Compounds

Compounds described herein are synthesized using standard synthetictechniques or using methods know in the art in combination with methoddescribed herein.

General synthetic method for preparing intermediates and compoundsdescribed herein is shown in Exemplary Scheme 1.

Compounds of formula C are formed by reacting compounds of formula Awith compound of formula B under known condensation conditions (See,e.g., Eur. J Org, Chem., 2004, 546-551, J. Org Chem., 2006, 71,5440-5447, Synthesis, 2003, 555-559, Eur. J. Org. Chem., 2006,3767-3770, Org. Lett., 2013, 15,1854-1857, J. Org. Chem, 2007, 72,9854-9856, Synlett, 2011, 1723-1726, Org. Lett., 2013, 15, 4564-4567,Eur. J. Org. Chem., 2006, 3767-3770).

In certain instances the reaction of compounds A and compounds B lead inone step to compounds C. In other instances two steps are needed to formcompounds C from compounds A and B. First step is the formation of thecondensation products followed by nucleophilic reaction underappropriate conditions.

Another general synthetic method for preparing starting materialsdescribed herein is shown in Exemplary Scheme 2.

Reductive amination reaction between Compounds of Formula D andCompounds of Formula F followed by nucleophilic substitution of thechloro group leads to Compounds of Formula F. On the other hand,formation of amide from Compounds of Formula D and Compounds of FormulaE, followed by nucleophilic substitution of the chloro group leads tocompounds of Formula G. The reaction of Compounds of Formula G usingchlorinating reagents such as POCl₃ under appropriate conditions giveCompounds of Formula H. Compounds of Formula H form via nucleophilicsubstitutions Compounds of Formula I or via carbon-carbon bond formationusing known methods such as Suzuki coupling reaction Compounds ofFormula 1.

General synthetic for preparing starting materials described herein isshown in Exemplary Scheme 3.

Exemplary starting materials useful in Exemplary Scheme 3 include:

As used herein, “EWG” refers to an electron withdrawing group. Asunderstood in the art, an electron withdrawing group is an atom or groupthat draws electron density from neighboring atoms towards itself,usually by resonance or inductive effects.

In some embodiments, the preparation of the compounds described hereinis made with the sequence of steps shown in Exemplary Scheme 4.

Compound 3 is prepared from the reaction of Reagents 1 and Reagent 2using knoevenagel condensation. Compound 4 is prepared by reactingCompound 3 with reagent A-L-XH. The formation Compounds of Formula 5from Compounds of Formula 4 is known in the art. Compounds of Formula 6are prepared by the coupling reaction of acid 5 and amines.

In some embodiments, the preparation of the compounds is made with thesequence of steps shown in Exemplary Scheme 5.

In some embodiments, the preparation of the compounds is made with thesequence of steps shown in Exemplary Scheme 6.

In some embodiments, the preparation of the compounds is made with thesequence of steps shown in Exemplary Scheme 7.

In some embodiments, the preparation of the compounds is made with thesequence of steps shown in Exemplary Scheme 8.

Non-limiting specific examples of A-L-XH in the compounds describedherein are illustrated in FIG. 1.

Non-limiting specific examples of R₃R₂NH in the compounds describedherein are illustrated in FIG. 2.

FIG. 3 provides non-limiting representative examples of substitutedchloropyridinecarboxaldehyde.

Compounds described herein are also prepared according to ExemplaryScheme 9.

Compounds of Formula 47 prepared as follows.

Compound 44 is prepared according to U.S. Pat. No. 7,816,524, which ishereby incorporated by reference. The chlorination of Compounds ofFormula 44 using chlorinating agent such as POCl₃ leads to Compounds ofFormula 45. Compounds of Formula 45 undergo nucleophile substitutionwith HX-L-A (as defined above) to yield Compounds of Formula 46.Compounds of Formula 47 reacts with N,N-Dimethyformamide dimethy acetalto give Compounds of Formula 48. Compounds of Formula 48 react withsubstituted hydrazine or substituted amidine to yield Compounds ofFormula 49 and Compounds of Formula 50, respectively.

FIG. 4 provides non-limiting representative examples of R₂R₁NH.

Compounds described herein are also prepared according to ExemplaryScheme 10.

Compounds of Formula 3 are prepared from the reaction of Reagents 1 andReagent 2 in appropriate solvent and appropriate temperature in thepresence of an amine. The acid of formula 4 can be prepare fromhydrolysis of Compounds of Formula 3 (X═COOEt) and subsequent amidecoupling leads to Compounds of Formula 5.

Non-limiting specific examples that can be prepared by the method setforth in Exemplary Scheme 10 include:

Compounds described herein are also prepared according to ExemplaryScheme 11.

The reductive amination of aldehyde or ketone reagents by3-amino-2,6-dichloropyridine, followed by formation of a 6-membered ringby nucleophilic attack on 2-chloro give Compounds of Formula 51.Nucleophilic attack by A-L-XH (as defined above) leads to Compounds ofFormula 52. The amide formation from the reaction of3-amino-2,6-dichloropyridine with acid or acid chloride derivative, andsubsequent cyclization as described for Compounds of Formula 51 giveCompounds of Formula 53.

Nucleophilic attack by A-L-XH (as defined above) leads to Compounds ofFormula 54. The chlorination of Compounds of Formula 54 usingchlorinating agent such as POCl₃ leads to Compounds of Formula 55.Compounds of Formula 55 undergo nucleophilic substitution with amines(R₁R₂NH as defined in FIG. 5) to yield Compounds of Formula 56 or C—Cbond formation reaction such as Suzuki coupling to yield Compounds ofFormula 57.

Compounds described herein are also prepared according to Scheme 1.2.

Compounds of Formula 59 are prepared as described above. Nucleophilicattack by A-L-XH (as defined in above) leads to Compounds of Formula 60.

Compounds described herein are also prepared according to Scheme 13.

Compounds of Formula 63 are prepared as described above.

FIG. 5 provides non-limiting representative examples of R₂R₁NH used inthe methods described herein.

Compounds described herein are also prepared according to Scheme 14.

Compounds of Formula C are formed by reacting Compounds of Formula Awith Compound of Formula B in the presence of base such as sodiumhydride.

In certain instances, the reaction of Compounds of Formula A andCompounds of Formula B lead in one step to Compounds of Formula D. Inother instances, two steps are needed to form Compounds of Formula D.First step is the formation of the amide products of Formula C followedby nucleophilic reaction under appropriate conditions.

Compounds of Formula E are formed by reacting Compounds of Formula Dwith known chlorinating agents. In certain instances, the treatment ofCompounds of Formula E with nucleophiles formed Compounds of Formula F.In other instances, the Suzuki type reaction of Compounds of Formula Ewith substituted boronic acid derivatives formed Compounds of Formula G.

Another general synthetic method for preparing starting materialsdescribed herein is shown in Exemplary Scheme 15.

Exemplary starting materials useful in Exemplary Scheme 5 include:

Another general synthetic method for preparing Compounds Formula III(A)described herein is shown in Exemplary Scheme 16.

Compound A1 reacts with compound A2 to form amide A3. Compound A3undergoes a ring closure under basic conditions to form A4. Nucleophilicattack on A4 with A-L-XH as defined above leads to compound A5.

Another general synthetic method for preparing Compounds of FormulaIII(A)(1) described herein is shown in Exemplary Scheme 17.

Compound A4 reacts with R—Br under basic condition to form A6.Nucleophilic attack on A6 with A-L-XH as defined above leads to compoundA7.

Exemplary R—Br useful in Exemplary Scheme 17 include:

Other specific non-limiting examples prepared by the methods describedherein include:

Certain Terminology

Unless otherwise stated, the following terms used in this applicationhave the definitions given below. The use of the term “including” aswell as other forms, such as “include”, “includes,” and “included,” isnot limiting. The section headings used herein are for organizationalpurposes only and are not to be construed as limiting the subject matterdescribed.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). By way ofexample only, a group designated as “C₁-C₄” indicates that there are oneto four carbon atoms in the moiety, i.e. groups containing 1 carbonatom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl, group, i.e., the alkyl group is selected from, amongmethyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and1-butyl.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylgroup is branched or straight chain. In some embodiments, the “alkyl”group has 1 to 10 carbon atoms, i.e. a C₁-C₁₀alkyl. Whenever it appearsherein, a numerical range such as “1 to 10” refers to each integer inthe given range; e.g., “1 to 10 carbon atoms” means that the alkyl groupconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, up to andincluding 10 carbon atoms, although the present definition also coversthe occurrence of the term “alkyl” where no numerical range isdesignated. In some embodiments, an alkyl is a C₁-C₆alkyl. In one aspectthe alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, or t-butyl. Typical alkyl groups include, but are in no waylimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl,

An “alkylene” group refers refers to a divalent alkyl radical. Any ofthe above mentioned monovalent alkyl groups may be an alkylene byabstraction of a second hydrogen atom from the alkyl. In someembodiments, an alkelene is a (C₁-C₆alkylene. In other embodiments, analkylene is a C₁-C₄alkylene. Typical alkylene groups include, but arenot limited to, —CH₂—, —CH(CH₃)—, —C(C₃)₂—, —C₂CH₂—, —CH₂CH(CH₃)—,—CH₂C(CH₃)₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and the like.

“Azacyclic” or “azacyclic ring” refers to a saturated, partiallyunsaturated, or aromatic 3-7 membered monocyclic ring or an 8-12membered fused bicyclic ring system containing at least one nitrogenatom. Such azacyclic rings may optionally contain from 1-2 additionalheteroatoms selected from N, O, and S as ring members, and mayoptionally be substituted to the extent such substitutions make chemicalsense.

“Deuteroalkyl” refers to an alkyl group where 1 or more hydrogen atomsof an alkyl are replaced with deuterium.

The tern “alkenyl” refers of a type of alkyl group in which at least onecarbon-carbon double bond is present. In one embodiment, an alkenylgroup has the formula —C(R)═CR₂, wherein R refers to the remainingportions of the alkenyl group, which may be the same or different. Insome embodiments, R is H or an alkyl. Non-limiting examples of analkenyl group include —CH═CH₂, —C(CH₃)═C₂, —CH═CHCH₃, —C(CH₃)—CHCH₃, and—CH₂CH═CH₂.

The term “alkynyl” refers to a type of alkyl group in which at least onecarbon-carbon triple bond is present. In one embodiment, an alkenylgroup has the formula —C≡C—R, wherein R refers to the remaining portionsof the alkynyl group. In some embodiments, R is H or an alkyl.Non-limiting examples of an alkynyl group include —C≡CH, —C≡CCH₃—C≡CCH₂CH₃, —CH₂C≡CH.

An “alkoxy” group refers to a (alkyl)O-group, where alkyl is as definedherein.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, where x is0 and y is 2, where x is 1 and y is 1, or where x is 2 and y is 0.

The term “aromatic” refers to a planar ring haying a delocalizedπ-electron system containing 4n+2 π electrons, where n is an integer.The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g.,phenyl) and heterocyclic aryl (or “heteroaryl” “heteroaromatic”) groups(e.g., pyridine). The term includes monocyclic or fused-ring polycyclic(i.e., rings which share adjacent pairs of carbon atoms) groups.

The term “carbocyclic” or “carbocycle” refers to a ring or ring systemwhere the atoms forming the backbone of the ring are all carbon atoms.The term thus distinguishes carbocyclic from “heterocyclic” rings or“heterocycles” in which the ring backbone contains at least one atomwhich is different from carbon. In some embodiments, at least one of thetwo rings of a bicyclic carbocycle is aromatic. In some embodiments,both rings of a bicyclic carbocycle are aromatic.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. In one aspect, aryl isphenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In someembodiments, an aryl is a C₆-C₁₆aryl. Depending on the structure, anaryl group is a monoradical or a diradical (i.e., an arylene group).

The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic,non-aromatic radical, wherein each of the atoms forming the ring (i.e.skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls arespirocyclic or bridged compounds. In some embodiments, cycloalkyls areoptionally fused with an aromatic ring, and the point of attachment isat a carbon that is not an aromatic ring carbon atom. Cycloalkyl groupsinclude groups having from 3 to 10 ring atoms. In some embodiments,cycloalkyl groups are selected from among cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. Insome embodiments, a cycloalkyl is a C₃-C₆cycloalkyl.

The term “halo” or, alternatively, “halogen” or “halide” means fluoro.chloro, bromo or iodo. In some enabodiments, halo is fluoro, chloro, orbromo.

The term “fluoroalkyl” refers to an alkyl in which one or more hydrogenatoms are replaced by a fluorine atom. In one aspect, a fluoralkyl is aC₁-C₆ fluoroalkyl.

The term “heteroalkyl” refers to an alkyl group in which one or moreskeletal atoms of the alkyl are selected from an atom other than carbon,e.g., oxygen, nitrogen (e.g, —NH—, —N(alkyl)-, sulfur, or combinationsthereof. A heteroalkyl is attached to the rest of the molecule at acarbon atom of the heteroalkyl. In one aspect, a heteroalkyl is aC₁-C₆heteroalkyl.

The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings(also known as heteroaryls) and heterocycloalkyl rings (also known asheteroalicyclic groups) containing one to four heteroatoms in thering(s), where each heteroatom in the rings) is selected from O, S andN, wherein each heterocyclic group has from 3 to 10 atoms in its ringsystem, and with the proviso that any ring, does not contain twoadjacent O or S atoms. Non-aromatic heterocyclic groups (also known asheterocycloalkyls) include rings having 3 to 10 atoms in its ring systemand aromatic heterocyclic groups include rings having 5 to 10 atoms inits ring system. The heterocyclic groups include benzo-fused ringsystems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl,morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl,pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl,dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl,dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl,imidazolidinyl 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl,3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl,isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl,1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups are either C-attached (or C-linked)or N-attached where such is possible. For instance, a group derived frompyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached). Further, a group derived from imidazole includesimidazol-1-yl or imidazol-1-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groupsinclude benzo-fused ring systems. Non-aromatic heterocycles areoptionally substituted with one or two oxo (═O) moieties, such aspyrrolidin-2-one. In some embodiments, at least one of the two rings ofa bicyclic heterocycle is aromatic. In some embodiments, both rings of abicyclic heterocycle are aromatic.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groupsinclude monocyclic heteroaryls and bicyclic heteroaryls. Monocyclicheteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl,thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizineindole, benzofuran, benzothiophene, indazole, benzimidazole, purine,quinolizine, quinoline, isoquinoline, cinnoline, phthalazine,quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In someembodiments, a heteroaryl contains 0-4 N atoms in the ring. In someembodiments, a heteroaryl contains 1-4 N atoms in the ring. In someembodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 Satoms in the ring. In some embodiments, a beteroaryl contains 1-4 Natoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments,heteroaryl is a C₁-C₉heteroaryl. In some embodiments, monocyclicheteroaryl is a C₁-C₅heteroaryl. In some embodiments, monocyclicheteroaryl is a 5-membered or 6-membered heteroaryl. In someembodiments, bicyclic heteroaryl is a C₆-C₉beteroaryl.

A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkylgroup that includes at least one heteroatom selected from nitrogen,oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused withan aryl or heteroaryl. In some embodiments, the heterocycloalkyl isoxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, piperidin-2-onyl,pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl,imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The term,heteroalicyclic also includes all ring forms of the carbohydrates,including but not limited to the monosaccharides, the disaccharides andthe oligosaccharides. In one aspect, a heterocycloalkyl is aC₂-C₁₀heterocycloalkyl. In another aspect, a heterocycloalkyl is aC₄-C₁₀heterocycloalkyl. In some embodiments, a heterocycloalkyl contains0-2 N atoms in the ring. In some embodiments, a heterocycloalkylcontains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

The term “bond” or “single bond” refers to a chemical bond between twoatoms,or two moieties when the atoms joined by the bond are consideredto be part of larger substructure. In one aspect, when a group describedherein is a bond, the referenced group is absent thereby allowing a bondto be formed between the remaining identified groups.

The term “moiety” refers to a specific segment, or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

The term “optionally substituted” or “substituted” means that thereferenced group is optionally substituted with one or more additionalgroup(s) individually and independently selected from halogen, —CN,—NH₂, —NH(alkyl), —N(alkyl)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl),—S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy,fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.In some other embodiments, optional substituents are independentlyselected from halogen, —CN, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H,—CO₂(C₁-C₄alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₄alkyl), —C(═O)N(C₁-C₄alkyl)₂,—S(═O)₂NH₂, —S(═O)₂NH(C₁-C₄alkyl), —S(═O)₂N(C₁-C₄alkyl)₂, C₁-C₄alkyl,C₃-C₆cycloalkyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl, C₁-C₄alkoxy,C₁-C₄fluoroalkoxy, —SC₁-C₄alkyl, —S(═O)C₁-C₄alkyl, and—S(═O)₂C₁-C₄alkyl. In some embodiments, optional substituents areindependently selected from halogen, —CN, —NH₂, —OH, —NH(CH₃), —N(CH₃)₂,—CH₃, —CH₂CH₃, —CF₃, —OCH₃, and —OCF₃. In some embodiments, substitutedgroups are substituted with one or two of the preceding groups. In someembodiments, an optional substituent on an aliphatic carbon atom(acyclic or cyclic) includes oxo (═O).

“Carboxylate bioisostere” or “carboxy bioisostere” as used herein refersto a moiety that is expected to be negatively charged to a substantialdegree at physiological pH. In certain embodiments, the carboxylatebioisostere is a moiety selected from the group consisting of:

and salts of the forgoing, wherein each R″ is independently H or anoptionally substituted member selected from the group consisting ofC₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ heteroalkyl, C₃₋₈ carbocyclic ring; orR″ is a C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, or C₃₋₁₀ heteroalkyl substitutedwith an optionally substituted C₃₋₈ carbocycli ring or C₃₋₈ heterocyclicring.

Amide bioisostere and ester bioisostere as used herein refer to amoities represented by the following examples:

wherein each R″ is independently H or an optionally substituted memberselected from the group consisting of C₁₋₁₀ alkyl, alkenyl, C₂₋₁₀heteroalkyl, C₃₋₈ carbocyclic ring; or R″ is a C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, or C₂₋₁₀ heteroalkyl substituted with an optionally substitutedC₃₋₈ carbocyclic ring or C₃₋₈ heterocyclic ring.

The compounds presented herein may possess one or more stereocenters andeach center may exist in the R or S configuration. The compoundspresented herein include all diastereomeric, enantiomeric, and, epimericforms as well as the appropriate mixtures thereof. Stereoisomers may beobtained, if desired, by methods known in the art such as, for example,the separation of individual stereoisomers by chiral chromatographiccolumns or by stereoselective synthesis.

A “quaternary amine” is a positively charged polyatomic ion of thestructure NR₄ ⁺, where R is an alkyl or aryl group. The four (4) Rgroups that make up the quaternary amine may be the same or differentand may be connected to one another. Quaternary amines can be preparedby the alkylation of tertiary amines, in a process calledquaternization, as well as by other methods known in the art.

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

The term “modulate” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the target, to limit the activity of the target, orto extend the activity of the target.

The term “modulator” as used herein, refers to a molecule that interactsa target either directly or indirectly. The interactions include, butare not limited to, the interactions of an agonist, partial agonist, aninverse agonist, antagonist, degrader, or combinations thereof. In someembodiments, a modulator is an antagonist. In some embodiments, amodulator is a degrader.

The terms “administer,” “administering”, “administration,” and the like,as used herein, refer to the methods that may be used to enable deliveryof compounds or compositions to the desired site of biological action.These methods include, but are not limited to oral routes, intraduodenalroutes, parenteral injection (including intravenous, subcutaneous,intraperitoneal, intramuscular, intravascular or infusion), topical andrectal administration. Those of skill in the art are familiar withadministration techniques that can be employed with the compounds andmethods described herein. In some embodiments, the compounds andcompositions described herein are administered orally.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered, which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result includesreduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case is optionallydetermined using techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound described herein, or a pharmaceuticallyacceptable salt thereof, and a co-agent, are both administered to apatient simultaneously in the form of a single entity or dosage. Theterm “non-fixed combination” means that the active ingredients, e.g. acompound described herein, or a pharmaceutically acceptable saltthereof, and a co-agent, are administered to a patient as separateentities either simultaneously, concurrently or sequentially with nospecific intervening time limits, wherein such administration provideseffective levels of the two compounds in the body of the patient. Thelatter also applies to cocktail therapy, e.g. the administration ofthree or more active ingredients.

The terms “kit” and “article of manufacture” are used as synonyms.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the Mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. In one aspect, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseaseor condition, preventing additional symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Pharmaceutical Compositions

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. Pharmaceutical compositions are formulatedin a conventional manner using one or more pharmaceutically acceptableinactive ingredients that facilitate processing of the active compoundsinto preparations that are used pharmaceutically. It is understood inthe art that proper formulation is dependent upon the route ofadministration chosen. A summary of pharmaceutical compositionsdescribed herein is found, for example, in Remington: The Science andPractice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack PublishingCompany, 1995); Hoover, John E., Remington's Pharmaceutical Sciences,Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L.,Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y, 1980;and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.(Lippincott Williams & Wilkins 1999), herein incorporated by referencefor such disclosure.

In some embodiments, the compounds described herein are administeredeither alone or in combination with pharmaceutically acceptablecarriers, excipients or diluents, in a pharmaceutical composition.Administration of the compounds and compositions described herein can beeffected by any method that enables delivery of the compounds to thesite of action. These methods include, though are not limited todelivery via enteral routes (including oral, gastric or duodenal feedingtube, rectal suppository and rectal enema), parenteral routes (injectionor infusion, including intraarterial, intracardiac, intradermal,intraduodenal, intramedullary, intramuscular, intraosseous,intraperitoneal, intrathecal, intravascular, intravenous, intravitreal,epidural and subcutaneous), inhalational, transdermal, transmucosal,sublingual, buccal and topical (including epicutaneous, dermal, enema,eye drops, ear drops, intranasal, vaginal) administration, although themost suitable route may depend upon for example the condition anddisorder of the recipient. By way of example only, compounds describedherein can be administered locally to the area in need of treatment, byfor example, local infusion during surgery, topical application such ascreams or ointments, injection, catheter, or implant. The administrationcan also be by direct injection at the site of a diseased tissue ororgan.

In some embodiments, pharmaceutical compositions suitable for oraladministration are presented as discrete units such as capsules, cachetsor tablets each containing a predetermined amount of the activeingredient; as a powder or granules, as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. In some embodiments, theactive ingredient is presented as a bolus, electuary or paste.

Pharmaceutical compositions which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. In some embodiments, the tabletsare coated or scored and are formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In some embodiments, stabilizers are added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or Dragee coatings for identification to characterize differentcombinations of active compound doses.

In some embodiments, pharmaceutical compositions are formulated forparenteral administration by injection, e.g., by bolus injection orcontinuous infusion. Formulations for injection may be presented in unitdosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. The compositions may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored inpowder form or in a freeze-dried (lyophilized) condition requiring onlythe addition of the sterile liquid carrier, for example, saline orsterile pyrogen-free water, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets of the kind previously described.

Pharmaceutical compositions for parent administration include aqueousand non-aqueous (oily) sterile injection solutions of the activecompounds which may contain antioxidants, buffers, bacteriostats andsolutes which render the formulation isotonic with the blood of theintended recipient; and aqueous and non-aqueous sterile suspensionswhich may include suspending agents and thickening agents. Suitablelipophilic solvents or vehicles include fatty oils such as sesame oil,or synthetic fatty acid esters, such as ethyl oleate or triglycerides,or liposomes. Aqueous injection suspensions may contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may alsocontain suitable stabilizers or agents which increase the solubility ofthe compounds to allow for the preparation of highly concentratedsolutions.

Pharmaceutical compositions may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds may beformulated with suitable polymeric or hydrophobic materials (forexample, as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

Pharmaceutical compositions may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter, polyethyleneglycol, or other glycerides.

Pharmaceutical compositions may be administered topically, that is bynon-systemic administration. This includes the application of a compoundof the present invention externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Pharmaceutical compositions suitable for topical administration includeliquid or semi-liquid preparations suitable for penetration through theskin to the site of inflammation such as gels, liniments, lotions,creams, ointments or pastes, and drops suitable for administration tothe eye, ear or nose. The active ingredient may comprise, for topicaladministration, from 0.001% to 10% w/w, for instance from 1% to 2% byweight of the formulation.

Pharmaceutical compositions for administration by inhalation areconveniently delivered from an insufflator, nebulizer pressurized packsor other convenient means of delivering an aerosol spray. Pressurizedpacks may comprise a suitable propellant such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Alternatively, foradministration by inhalation or insufflation, pharmaceuticalpreparations may take the form of a dry powder composition, for examplea powder mix of the compound and a suitable powder base such as lactoseor starch. The powder composition may be presented in unit dosage form,in for example, capsules, cartridges, gelatin or blister packs fromwhich the powder may be administered with the aid of an inhalator orinsufflator.

It should be understood that in addition to the ingredients particularlymentioned above, the compounds and compositions described herein mayinclude other agents conventional in the art having regard to the typeof formulation in question, for example those suitable for oraladministration may include flavoring agents.

Methods of Dosing and Treatment Regimens

In one embodiment, the compounds described herein, or a pharmaceuticallyacceptable salt thereof, are used in the preparation of medicaments forthe treatment of diseases or conditions in a mammal that would benefitfrom inhibiting POL1 transcription. Methods for treating any of thediseases or conditions described herein in a mammal in need of suchtreatment, involves administration of pharmaceutical compositions thatinclude at least one compound described herein or a pharmaceuticallyacceptable salt, active metabolite, prodrug, or pharmaceuticallyacceptable solvate thereof, in therapeutically effective amounts to saidmammal.

In some embodiments, the invention provides methods of treatingconditions associated with polymerase 1 transcription, comprising:administering to a patient in need thereof an effective amount of acompound of the invention. In another embodiment, the invention providesa method of inhibiting polymerase I transcription: comprising,contacting the enzyme with a compound of the invention. In a furtherembodiment, the invention provides a method of inhibiting polymerasetranscription: comprising, administering a first compound to a subjectthat is converted in vivo to a compound of the invention.

“Conditions associated with polymerase I transcription” includedisorders and diseases in which the inhibition of polymerase Itranscription provides a therapeutic benefit, such as cancer,allergy/asthma, diseases and conditions of the immune system,inflammation, disease and conditions of the central nervous system(CNS), cardiovascular disease, viral infections, dermatological disease,and diseases and conditions related to uncontrolled angiogenesis, andthe like. Where general terms are used herein to describe conditionsassociated with polymerase I transcription it is understood that themore specifically described conditions mentioned in the variousdiagnostic manuals and other materials are included within the scope ofthis invention.

The term “cancer,” as used herein refers to an abnormal growth of cells,which tend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread). The types of cancer include, but is not limitedto, solid tumors (such as those of the bladder, bowel, brain, breast,endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary,pancreas or other endocrine organ (thyroid), prostate, skin (melanoma)or hematological tumors (such as the leukemias). See, Ding X Z et al.,Anticancer Drugs. 2005 June; 16(5):467-73, Review; Chen X et al., ClinCancer Res. 2004 Oct, 1; 10(19):6703-9, each of which are incorporatedby reference herein in their entirety.

For example, it is understood that the treatment of cancer includestreatment of all neoplasia, regardless of their histopathologicalappearance. Particularly, the cancers that can be treated include, butare not limited to, cancer of blood, including myelofibrosis, leukemia(including acute myelogenous leukemia, chronic myelogenous leukemia,acute lymphocytic leukemia, chronic mphocytie leukemia), cancer of theskin, including melanoma, basal cell carcinoma, and squamous cellcarcinoma, bone, liver, lung (including small-cell lung tumor, nonsmall-cell lung cancer and bronchioalveolar cancer), brain, breast,prostate, larym, gall bladder, pancreas, rectum, bile duct, parathyroid,thyroid, adrenal, neural tissue, bladder, spleen, head and neck,included the jaw, mouth, and nose, colon, stomach, testes, esophagus,uterus, cervix and vulva, colorectal, bronchi, bile duct, bladder,kidney, ovary, pancreas, multiple myeloma, lymphomas, basal cellcarcinoma, squamous cell carcinoma of both ulcerating and papillarytype, osteo sarcoma, Ewing's sarcoma, veticulum cell sarcoma, myeloma,giant cell tumor, islet cell tumor, acute and chronic lymphocytic andgranulocytic tumors, hairy-cell tumor, adenoma, hyperplasia, medullarycarcinoma, pheochromocytoma, mucosal neuronms, intestinalganglioneuromas, hyperplastic corneal nerve tumor, emarfanoid habitustumor, Wilm's tumor, seminoma, ovarian tumor, leiomyornater tumor,cervical dysplasia and in situ carcinoma, neuroblastoma, retinoblastoma,myelodysplastic syndrome, mycosis fungicide, rhabdomyosarcoma,astrocytoma, non-Hodgkin's lymphoma, Kaposi's sarcoma, osteogenic andother sarcoma, malignant hypercalcemia, polycythermia vera,adenocarcinoma, glioblastoma multiforma, glioma, lymphomas, epidermoidcarcinomas, and other carcinomas and sarcomas.

Benign tumors may also be treated by the compounds of the presentinvention and include, but are not limited to, hemangiomas,hepatocellular adenoma, cavernous haemangioma, focal nodularhyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bileduct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas,myxomas, nodular regenerative hyperplasia, trachomas, pyogenicgranulomas, and the like, and hamartoma conditions such as Peutz-JeghersSyndrome (PJS), Cowden disease, Barmayan-Riley-Ruvalcaba Syndrome(BRRS), Proteus syndrome, Lhermitte-Duclos disease and TuberousSclerosis (TSC).

The compounds of the present invention may also be used to treatabnormal cell proliferation due to insults to body tissue duringsurgery. These insults may arise as a result of a variety of surgicalprocedures such as joint surgery, bowel surgery, and cheloid scarring.Diseases that produce fibrotic tissue include emphysema. Repetitivemotion disorders that may be treated using the present invention includecarpal tunnel syndrome.

The compounds of the invention may also be useful in the prevention ofrestenosis that is the control of undesired proliferation of normalcells in the vasculature in response to the introduction of stents inthe treatment of vasculature disease.

Proliferative responses associated with organ transplantation that maybe treated using Pol I transcription inhibitors of the invention includeproliferative responses contributing to potential organ rejections orassociated complications. Specifically, these proliferative responsesmay occur during transplantation of the heart, lung, liver, kidney, andother body organs or organ systems.

The compounds of the invention may also be useful the treatment ofabnormal angiogenesis including the abnormal angiogenesis accompanyingrheumatoid arthritis, ischemic-reperfusion related brain edema andinjury, cortical ischemia, ovarian hyperplasia and hypervascularity,(polycystic ovary syndrome), endometriosis, psoriasis, diabeticretinopaphy, and other ocular angiogenic diseases such as retinopathy ofprematurity (retrolental fibroplastic), macular degeneration, cornealgraft rejection, neuroscular glaucoma, Oster Webber syndrome,retinal/choroidal neuvascularization and corneal neovascularization,Best's disease, myopia, optic pits, Stargart's diseases, Pagets disease,vein occlusion, artery occlusion, sickle cell anemia, sarcoid, syphilis,pseudoxanthoma elasticum carotid abstructive diseases, chronicuveitis/vitritis, mycobacterial infections, Lyme's disease, systemiclupus erythematosis, retinopathy of prematurity, Eales disease, diabeticretinopathy, macular degeneration, Bechets diseases, infections causinga retinitis or chroiditis, presumed ocular histoplasmosis, parsplanitis, chronic retinal detachment, hyperviscosity syndromes,toxoplasmosis, trauma and post-laser complications, diseases associatedwith rubesis (neovascularization of the angle), diseases caused by theabnormal proliferation of fibrovascular or fibrous tissue including allforms of proliferative vitreoretinopathy, atopic keratitis, superiorlimbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea,phylectenulosis, diabetic retinopathy, retinopathy of prematurity,cortical graft rejection, Mooren's ulcer, Terrien's marginaldegeneration, marginal keratolysis, polyarteritis, Wegener sarcoidosis,scleritis, periphigoid radial keratotomy, neovascular glaucoma andretrolental fibroplasia, syphilis, Mycobacteria infections, lipiddegeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpessimplex infections, Herpes zoster infections, protozoan infections, andKaposi sarcoma, Alzheimer's disease, Parkinson's disease amyotrophiclateral sclerosis (ALS), epilepsy, seizures, Huntington's disease,polyglutamine diseases, traumatic brain injury, ischemic andhemorrhaging stroke, cerebral ischemias or neurodegenerative disease,including apoptosis-driven neurodegenerative disease, caused bytraumatic injury, acute hypoxia, ischemia or glutamate neurotoxicity.

For example, it is understood that treatments of inflammation include,but are not limited to, acute pancreatitis, chronic pancreatitis,asthma, allergies, chronic obstructive pulmonary disease, adultrespiratory distress syndrome and chronic inflammatory diseasesassociated with uncontrolled angiogenesis, inflammatory bowel diseasessuch as Crohn's disease and ulcerative colitis, psoriasis, sarcoidois,and rheumatoid arthritis, sarcoidosis, and multisystem granulomatousdisorder.

For example, it is understood that treatment of autoimmune includes, butis not limited to, glomerulonephritis, rheumatoid arthritis, systemiclupus erytheinatosus, scleroderma, chronic thyroiditis, Graves' disease,autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmuneneutropenia, thrombocytopenia, atopic dermatitis, chronic activehepatitis, myasthenia gram, multiple sclerosis, inflammatory boweldisease, ulcerative colitis, Crohn's disease, psoriasis, graft vs. hostdisease, multiple sclerosis, or Sjoegren's syndrome.

In certain embodiments, the compositions containing the compound(s)described herein are administered for prophylactic and/or therapeutictreatments. In certain therapeutic applications, the compositions areadministered to a patient already suffering from a disease or condition,in an amount sufficient to cure or at least partially arrest at leastone of the symptoms of the disease or condition. Amounts effective forthis use depend on the severity and course of the disease or condition,previous therapy, the patient's health status, weight, and response tothe drugs, and the judgment of the treating physician. Therapeuticallyeffective amounts are optionally determined by methods including, butnot limited to, a dose escalation and/or dose ranging clinical trial.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in patients, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician. In one aspect, prophylactic treatments include administeringto a mammal, who previously experienced at least one symptom of thedisease being treated and is currently in remission, a pharmaceuticalcomposition comprising a compound described herein, or apharmaceutically acceptable salt thereof, in order to prevent a returnof the symptoms of the disease or condition.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of the compounds areadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In certain embodiments wherein a patient's status does improve, the doseof drug being administered is temporarily reduced or temporarilysuspended for a certain length of time (i.e., a “drug holiday”). Inspecific embodiments, the length of the drug holiday is between 2 daysand 1 year, including by way of example only, 2 days, 3 days, 4 days, 5days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, ormore than 28 days. The dose reduction during a drug holiday is, by wayof example only, by 10%100%, including by way of example only 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, and 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, in specificembodiments, the dosage or the frequency of administration, or both, isreduced, as a function of the symptoms, to a level at which the improveddisease, disorder or condition is retained. In certain embodiments,however, the patient requires intermittent treatment on a long-termbasis upon any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount variesdepending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight, sex) of thesubject or host in need of treatment, but nevertheless is determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and the subject or hostbeing treated.

In general, however, doses employed for adult human treatment aretypically in the range of 0.01 mg-5000 mg per day. In one aspect, dosesemployed for adult human treatment are from about 1 mg, to about 1000mug per day. In one embodiment, the desired dose is convenientlypresented in a single dose or in divided doses administeredsimultaneously or at appropriate intervals, for example as two, three,four or more sub-doses per day.

In one embodiment, the daily dosages appropriate for the compounddescribed herein, or a pharmaceutically acceptable salt thereof, arefrom about 0.01 to about 50 mg/kg per body weight. In some embodiments,the daily dosage or the amount of active in the dosage form are lower orhigher than the ranges indicated herein, based on a number of variablesin regard to an individual treatment regime. In various embodiments, thedaily and unit dosages are altered depending on a number of variablesincluding, but not limited to, the activity of the compound used, thedisease or condition to be treated, the mode of administration, therequirements of the individual subject, the severity of the disease orcondition being treated, and the judgment of the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens aredetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ and the ED₅₀. The dose ratio between the toxic andtherapeutic effects is the therapeutic index and it is expressed as theratio between LD₅₀ and ED₅₀. In certain embodiments, the data obtainedfrom cell culture assays and animal studies are used in formulating thetherapeutically effective daily dosage range and/or the therapeuticallyeffective unit dosage amount for use in mammals, including humans. Insome embodiments, the daily dosage amount of the compounds describedherein lies within a range of circulating concentrations that includethe ED₅₀ with minimal toxicity. In certain embodiments, the daily dosagerange and/or the unit dosage amount varies within this range dependingupon the dosage form employed and the route of administration utilized.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound described herein, or apharmaceutically acceptable salt thereof, is: (a) systemicallyadministered to the mammal; and/or (b) administered orally to themammal; and/or (c) intravenously administered to the mammal; and/or (d)administered by injection to the mammal; and/or (e) administeredtopically to the mammal; and/or (f) administered non-systemically orlocally to the mammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce a day; or (ii) the compound is administered to the mammal multipletimes over the span of one day.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours; (iv) the compound isadministered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

In certain instances, it is appropriate to administer at least onecompound described herein, or a pharmaceutically acceptable saltthereof, in combination with one or more other therapeutic agents. Incertain embodiments, the pharmaceutical composition further comprisesone or more anti-cancer agents.

In one embodiment, the therapeutic effectiveness of one of the compoundsdescribed herein is enhanced by administration of an adjuvant (i.e., byitself the adjuvant has minimal therapeutic benefit, but in combinationwith another therapeutic agent, the overall therapeutic benefit to thepatient is enhanced). Or, in some embodiments, the benefit experiencedby a patient is increased by administering one of the compoundsdescribed herein with another agent (which also includes a therapeuticregimen) that also has therapeutic benefit.

A wide variety of therapeutic agents may have a therapeutic additive orsynergistic effect with the compounds according to the presentinvention. Combination therapies that comprise one or more compounds ofthe present invention with one or more other therapeutic agents can beused, for example, to: (1) enhance the therapeutic effect(s) of the oneor more compounds of the present invention and/or the one or more othertherapeutic agents; (2) reduce the side effects exhibited by the one ormore compounds of the present invention and/or the one or more othertherapeutic agents; and/or (3) reduce the effective dose of the one ormore compounds of the present invention and/or the one or more othertherapeutic agents. It is noted that combination therapy is intended tocover when agents are administered before or after each other(sequential therapy) as well as when the agents are administered at thesame time.

Examples of such therapeutic agents that may be used in combination withthe present compounds include, but are not limited to, anti-cellproliferation agents, anticancer agents, alkylating agents, antibioticagents, antimetabolic agents,hormonal agents, plant-derived agents, andbiologic agents.

Anti-cell proliferation agents useful in combination with the compoundsof the present invention include, but are not limited to, retinoid acidand derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN™ protein,ENDOSTATIN™ protein, suramin, squalamine, tissue inhibitor ofmetalloproteinase-I, tissue inhibitor of metalloproteinase-2,plasminogen activator inhibitor-1, plasminogen activator inhibitor-2,cartilage-derived inhibitor, paclitaxel, platelet factor 4, protaminesulphate (clupeine), sulphated chitin derivatives (prepared from queencrab shells), sulphated polysaccharide peptidoglycan complex (sp-pg),staurosporine, modulators of matrix metabolism, including for example,proline analogs ((1-azetidine-2-carboxylic acid (LACA),cishydroxyproline, d,1-3,4-dehydroproline, thiaproline,beta-aminopropionitrile fumarate,4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone, methotrexate, mitoxantrone,heparin, interferons, 2 macroglobulin-serum, chimp-3, chymostatin,beta.-cyclodextrin tetradecasulfate, eponemycin; fumagillin, gold sodiumthiomalate, d-penicillamine (CDPT), beta-1-anticollagenase-serum,alpha-2-antiplasmin, bisantrene, lobenzarit disodium,n-(2-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”,thalidomide, angostatic steroid, cargboxynaminolmidazole,metalloproteinase inhibitors such as BB94. Other anti-angiogenesisagents that may be used include antibodies, preferably monoclonalantibodies against these angiogenic growth factors: bFGF, aFGF, FGF-5,VEGF isoforms, VEGF-C, HGF/SF and Ang-1 ,Ang-2.

Inhibitors of mTOR, PI3K, MEK, MAPK, PIM or ERK kinases are useful incombination with the compounds of the present invention. Specifically,(R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dioneuseful in combination with the compounds of the present invention.Inhibitors of Hedgehog kinase are useful in combination with thecompounds of the present invention. Proteasome inhibitors, in particularbortezomib is useful in combination with the compounds of the presentinvention.

NAE inhibitors, VPS34 inhibitors, Aurora kinase, including Aurora Ainhibitors, and EGFR inhibitors (both antibodies and kinase inhibitors)are useful in combination with the compounds of the present invention.

Alkylating agents useful in combination with the compunds disclosedherein include, but are not limited to, bischloroethylamines (nitrogenmustards, e.g. chlorambucil, cyclophosphamide, ifosfamide,mechlorethamine, melphalan, uracil mustard), aziridines (e.g. thiotepa),alkyl alkone solfonates (e.g. busulfan), nitrosoureas (e.g. carmustine,lomustine, streptozocin), nonclassic alkylating agents (altretamine,dacarbazine, and procarbazine), platinum compounds (carboplastin andcisplatin). Combination therapy including a polymerase I inhibitor andan alkylating agent is expected to have therapeutic synergistic effectsin the treatment of cancer and reduce sides affects associated withthese chemotherapeutic agents.

Examples of antibiotic agents useful in combination with the compoundsdisclosed herein include, but are not limited to, anthracyclines (e.g.doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione),mitomycin C, bleomycin, dactinomycin, plicatomycin. These antibioticagents interfere with cell growth by targeting different cellularcomponents.

Antimetabolic agents useful in combination with the compounds disclosedherein include, but are not limited to, fluorouracil (5-FU), floxuridine(5-FUdR), methotrexate, leucovorin, hydroxyurea, thioguanine (6-TG),mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine phosphate,cladribine (2-CDA), asparaginase, and gemcitabine. Combination therapyincluding a compound disclosed herein and an antimetabolic agent isexpected to have therapeutic synergistic effects on cancer and reducesides affects associated with these chemotherapeutic agents.

Hormonal agents useful in combination with the compounds disclosedherein include synthetic estrogens (e.g. diethylstibestrol),antiestrogens (e.g. tamoxifen, toremifene, fluoxymesterol andraloxifene), antiandrogens (bicalutamide, nilutamide, and flutamide),aromatase inhibitors (e.g., aminoglutethimide, anastrozole andtetrazole), ketoconazole, goserelin acetate, leuprolide, megestrolacetate and mifepristone. Combination therapy including a compounddisclosed herein and a hormonal agent is expected to have therapeuticsynergistic effects on cancer and reduce sides affects associated withthese chemotherapeutic agents.

Plant-derived agents useful in combination with the compounds disclosedherein include, but are not limited to, vinca alkaloids (e.g.,vincristine, vinblastine, vindesine, vinzolidine and vinorelbine),podophyllotoxins (e.g. etoposide (VP-16) and teniposide (VM-26)),taxanes (e.g., paclitaxel and docetaxel). These plant-derived agentsgenerally act as antimitotic agents that bind to tubulin and inhibitmitosis. Podophyllotoxins such as etoposide are believed to interferewith DNA synthesis by interacting with topoisomerase II, leading to DNAstrand scission. Combination therapy including a compound disclosedherein and a plant-derived agent is expected to have therapeuticsynergistic effects on cancer and reduce sides affects associated withthese chemotherapeutic agents

In any case, regardless of the disease, disorder or condition beingtreated, the overall benefit experienced by the patient is simply beadditive of the two therapeutic agents or the patient experiences asynergistic benefit.

In certain embodiments, different therapeutically-effective dosages ofthe compounds disclosed herein will be utilized in formulatingpharmaceutical composition and/or in treatment regimens when thecompounds disclosed herein are administered in combination with one ormore additional agent, such as an additional therapeutically effectivedrug, an adjuvant or the like. Therapeutically-effective dosages ofdrugs and other agents for use in combination treatment regimens isoptionally determined by means similar to those set forth hereinabovefor the actives themselves. Furthermore, the methods ofprevention/treatment described herein encompasses the use of metronomicdosing, i.e., providing more frequent, lower doses in order to minimizetoxic side effects. In some embodiments, a combination treatment regimenencompasses treatment regimens in which administration of a compounddescribed herein, or a pharmaceutically acceptable salt thereof, isinitiated prior to, during, or after treatment with a second agentdescribed herein, and continues until any time during treatment with thesecond agent or after termination of treatment with the second agent. Italso includes treatments in which a compound described herein, or apharmaceutically acceptable salt thereof, and the second agent beingused in combination are administered simultaneously or at differenttimes and/or at decreasing or increasing intervals during the treatmentperiod. Combination treatment further includes periodic treatments thatstart and stop at-arious times to assist with the clinical management ofthe patient.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, is modified inaccordance with a variety of factors (e.g. the disease, disorder orcondition from which the subject suffers; the age, weight, sex, diet,and medical condition of the subject). Thus, in some instances, thedosage regimen actually employed varies and, in some embodiments,deviates from the dosage regimens set forth herein.

For combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drugemployed, on the specific drug employed, on the disease or conditionbeing treated and so forth. In additional embodiments, whenco-administered with one or more other therapeutic agents, the compoundprovided herein is administered either simultaneously with the one ormore other therapeutic agents, or sequentially.

In combination therapies, the multiple therapeutic agents (one of whichis one of the compounds described herein) are administered in any orderor even simultaneously. If administration is simultaneous, the multipletherapeutic agents are, by way of example only, provided in a single,unified form, or in multiple forms (e.g., as a single pill or as twoseparate pills).

The compounds described herein, or a pharmaceutically acceptable saltthereof, as well as combination therapies, are administered before,during or after the occurrence of a disease or condition, and thetiming, of administering the composition containing a compound varies.Thus, in one embodiment, the compounds described herein are used as aprophylactic and are administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. In another embodiment, thecompounds and compositions are administered to a subject during or assoon as possible after the onset of the symptoms. In specificembodiments, a compound described herein is administered as soon as ispracticable after the onset of a disease or condition is detected orsuspected, and for a length of time necessary for the treatment of thedisease. In some embodiments, the length required for treatment varies,and the treatment length is adjusted to suit the specific needs of eachsubject. For example, in specific embodiments, a compound describedherein or a formulation containing the compound is administered for atleast 2 weeks, about 1 month to about 5 years.

In some embodiments, a compound described herein, or a pharmaceuticallyacceptable salt thereof, is administered in combination withchemotherapy, hormone blocking therapy, radiation therapy, monoclonalantibodies, or combinations thereof.

Chemotherapy includes the use of one or more anti-cancer agents.

EXAMPLES

The following examples are provided for illustrative purposes only andnot to limit the scope of the claims provided herein.

Having now generally described the invention, the same will be morereadily understood through reference to the following examples which areprovided by way of illustration, and are not intended to be limiting ofthe present invention, unless specified.

Example 1

A mixture of SM3 (648 mg, 4 mmol) in SOCl₂ (20 ml) was refluxed for 4 h.and concentrated to get the aryl chloride (Compound 1). To a solution of2-chloropyridin-3-amine (512 mg, 4 mmol) in dry THF (20 ml) was added60% NaH (480 mg, 12 mmol) at ice bath and, stirred at ice bath for 0.5h.

A solution of the acyl chloride in dry THF (10 mL) was added and thereaction mixture was stirred at room temperature overnight. The mixturewas diluted with EtOAc and washed with water, dried over Na₂SO₄,concentrated and purified by silica gel column (PE/EtOAc=5:1˜2:1) to get1H-Benzoimidazole-2-carboxylic acid (2-chloro-pyridine-3-yl)-amide(Compound 2) (320 mg, 32% yield) as gray solid. LC-MS: 273.1 [M+1]⁺

Example 2

A mixture of Compound 2 (320 mg, 1.17 mmol), Pd₂(dba)₃ (120 mg, 0.23mmol), Xantphos (130 mg, 0.23 mmol) and K₂CO (242 mg, 1.75 mmol) indioxane (15 ml) was heated by microwave at 150° C. for 1 h. Aftercooling, the mixture was poured into water, filtered and washed withEtOAc to get Compound 3 (270 mg, 82% yield) as gray solid. LC-MS: 237.2[M+1]⁺.

Example 3

A mixture of Compound 3 (230 mg, 0.97 mmol) in POCl₃ (10 ml) was stirredat refluxing for 3 h. After cooling, the mixture was concentrated washedwith EtOAc to get Compound 4 (210 mg, 85%yield) as gray solid. LC-MS;255.2 [M+1]⁺.

Example 4

A mixture of Compound 4 (54 mg, 0.21 mmol), Pd₂(dba)₃ (22.2 mg, 0.042mmol), Xantphos (23.6 mg, 0.042 mmol), K₂CO₃ (43 mg, 0.315 mmol) andN1,N1-dimethylethane-1,2-diamine (38 mg, 0.42 mmol) in dioxane (2 ml)was stirred by microwave at 150° C. for 1 h. After cooling, the mixturewas diluted with EtOAc, washed with water, concentrated and purified bypre-HPLC to get Compound 5 (16 mg, 25% yield) as pale yellow solid.LC-MS: 307.2 [M+1]⁺.

Example 5

Compound 6 is prepared according to the procedure described in Example4: Yield=32%, 21 mg, pale yellow solid. LC-MS: 319.2 [M+1]⁺.

Example 6

Compound 7 is prepared according to the procedure described in Example4: Yield=33%, 24 mg, pale yellow solid. LC-MS: 333.2 [M+1]⁺.

Example 7

Compound 8 is prepared according to the procedure described in Example4: Yield=33%, 23 mg, pale yellow solid: LC-MS: 333.4 [M+1]⁺.

Example 8

Compound 9 is prepared according to the procedure outlined in Example 4:Yield=32%, 380 mg, white solid. LC-MS: 286.9 [M+1]⁺.

Example 9

Compound 10 is prepared according to the procedure outlined in Example2: Yield=98%, 362 mg, off-white solid. LC-MS: 251.2 [M+1]⁺.

Example 10

Compound 11 is prepared according to the procedure outlined in Example3: Yield=98%, 380 mg, brown solid. LC-MS: 269.2 [M+1]⁺.

Example 11

Compound 12 is prepared according to the procedure outlined in Example4: Yield=30%, 30 mg, pale yellow solid. LC-MS: 347.2 [M+1]⁺.

Example 12

Compound 13 is prepared according to the procedure outlined in Example4: Yield=33%, 32 mg, pale yellow solid. LC-MS: 321.2 [M+1]⁺.

Example 12

Compound 14 is prepared according to the procedure outlined in Example4; Yield=28%, 28 mg, gray solid. LC-MS: 347.2 [M+1]⁺.

Example 13

Compound 15 is prepared according to the procedure outlined in Example4: Yield=18%, 18 mg, gray solid. LC-MS: 347.2 [M+1]⁺.

Example 14

Compound 16 is prepared according to the procedure outlined in Example1: Yield=79%, 900 mg, gray solid. LC-MS: 309.1 [M+1]⁺.

Example 15

Compound 17 is prepared according to the procedure outlined in Example2: Yield=92%, 365 mg, gray solid. LC-MS: 271.1 [M+1]⁺.

Example 16

Compound 18 is prepared according to the procedure outlined in Example3: Yield=98%, 380 mg, brown solid. LC-MS: 289.1 [M+1]⁺.

Example 17

Compound 19 is prepared according to the procedure outlined in Example4: Yield=29%, 29 mg, gray solid. LC-MS: 367.2 [M+1]⁺.

Example 18

Compound 20 is prepared according to the procedure outlined in Example4: Yield=20%, 18 mg, gray solid. LC-MS: 341.1 [M+1]⁺.

Example 19

Compound 21 is prepared according to the procedure outlined in Example4: Yield=17%, 17 mg, gray solid. LC-MS: 367.2 [M+1]⁺.

Example 20

Compound 22 is prepared according to the procedure outlined in Example4: Yield=27% , 27 mg, gray solid. LC-MS: 367.2 [M+1]⁺.

Example 21

Compound 23 is prepared according to the procedure outlined in Example1: Yield=69%, 690 mg, gray solid. LC-MS: 274.1 [M+1]⁺.

Example 22

Compound 24 is prepared according to the procedure outlined in Example2: Yield=76%, 230 mg, gray solid. LC-MS: 238.2 [M+1]⁺.

Example 23

Compound 25 is prepared according to the procedure outlined in Example3: Yield=99%, 250 mg, brown solid. LC-MS: 256.2 [M+1]⁺.

Example 24

Compound 26 is prepared according to the procedure outlined in Example4: Yield=26%, 20 mg, gray solid. LC-MS: 334.0 [M+1]⁺.

Example 25

Compound 27 is prepared according to the procedure outlined in Example4: Yield=22%, 16 mg, gray solid. LC-MS: 308.2 [M+1]⁺.

Example 26

Compound 28 is prepared according to the procedure outlined in Example4: Yield=23% 18 mg, gray solid. LC-MS: 334.2 [M+1]⁺.

Example 27

Compound 29 is prepared according to the procedure outlined in Example4: Yield=28%, 23 mg, gray solid. LC-MS: 334.2 [M+1]⁺.

Example 28

Compound 30 is prepared according to the procedure outlined in Example1: Yield=65%, 520 mg, gray solid. LC-MS: 274.1 [M+1]⁺.

Example 29

Compound 31 is prepared according to the procedure outlined in Example2: Yield=97%, 270 mg, gray solid. LC-MS: 238.2 [M+1]⁺.

Example 30

Compound 32 is prepared according to the procedure outlined in Example3: Yield=92%, 266 mg, brown solid. LC-MS: 255.9 [M+1]⁺.

Example 31

Compound 33 is prepared according to the procedure outlined in Example4: Yield=26%, 20 mg, gray solid. LC-MS: 334.3 [M+1]⁺.

Example 32

Compound 34 is prepared according to the procedure outlined in Example4: Yield=22%, 16 mg, gray solid. LC-MS: 308.3 [M+1]⁺.

Example 33

Compound 35 is prepared according to the procedure outlined in Example4: Yield=23%, 18 mg, gray solid. LC-MS: 334.2 [M+1]⁺.

Example 34

Compound 36 is prepared according to the procedure outlined in Example4: Yield=28%, 23 mg, gray solid. LC-MS: 334.2 [M+1]⁺.

Example 35

Compound 37 is prepared according to the procedure outlined in Example1: Yield=76%, 740 mg, brown solid. LC-MS: 307.1 [M+1]⁺.

Example 36

Compound 38 is prepared according to the procedure outlined in Example2; Yield=71%, 220 mg, brown solid. LC-MS: 271.1 [M+1]⁺.

Example 37

Compound 39 is prepared according to the procedure outlined in Example4: Yield=40%, 28 mg, yellow solid. LC-MS: 349.1 [M+1]⁺.

Example 38

Compound 40 is prepared according to the procedure outlined in Example4: Yield=32%, 23 mg, yellow solid. LC-MS: 323.0 [M+1]⁺.

Example 39

A solution of compound 38 (370 mg, 1.37 mmol) and N-Methylhomopiperazine(313 mg, 2.75 mmol) in NMP (15 mL) was stirred at 200° C. by microwavefor 7 h. The mixture was concentrated and the residue was Washed withMeOH to get2-(4-Methyl-[1,4]diazepan-1-yl)-5H-1,5,7,11b-tetraaza-benzo[c]fluoren-6-one(compound 41) (260 mg, Yield=54%) as brown solid. LC-MS: 349.1 [M+1]⁺.

Example 40

Compound 42 is prepared according to the procedure described in Example38: Yield=28%, 16 mg, yellow solid. LC-MS: 349.3 [M+1]⁺.

Example 41

Compound 43 is prepared according to the procedure described in Example3: Yield=98%, 270 mg, brown solid. LC-MS: 367.3 [M+1]⁺.

Example 42

A suspension of Compound 43 (70 mg, 0.191 mmol) CH₃NH₂/EtOH (2M, 2 ml)was heated to reflux for 16 h. After cooling, the mixture wasconcentrated, and the residue was added water and stirred at r.t. for 1h, filtered, washed with CH₃CN to get the desired product (68 mg, 98%yield) as yellow solid. LC-MS: 362.3 [M+1]⁺.

Example 43

Compound 45 is prepared according to the procedure described in Example41: LC-MS: Rt=1.06 min, 392.4 [M+1]⁺

Example 44

To a solution of Compound SM5 (0.96 g, 5 mmol) and Compound SM6 (1.02 g,5 mmol) in 2-(20 mL) in 2-Methoxyethanol (8 mL) was added Et₃N (2 mL, 15mmol) and the mixture was stirred at refluxing for 18 h. After cooling,the mixture was filtered and washed with EtOH to get Compound 46 (940mg, 55% yield) as brown solid. LC-MS: 342.3 [M+1]⁺.

Example 45

To a suspension of Compound 46 (50 mg, 0.147 mmol) in EtOH (2 mL) wasadded N1,N1-dimethylethane-1,2-diamine (0.2 mL, 2.14 mmol and themixture was stirred at refluxing for 5 h. After cooling, the mixture wasfiltered and washed with EtOH to give Compound 47 (30 mg, 53% yield) asyellow solid. LC-MS: Rt=1.153 min, 384.2 [M+1]⁺.

Example 46

To a suspension of Compound 46 (0.6 g, 1.76 mmol) in EtOH (10 mL, 1:1v/v) was 4N NaOH (aq., 2.2 mL, 8.8 mmol) and the mixture was stirred at60° C. for 30 min. The mixture was acidified to pH 6 by addition of 2 NHCl and stirred at r.t. for 30 min, the mixture was filtered and washedwith water, dried to give Compound 48 (540 mg, 98% yield) as a yellowsolid. LC-MS: Rt=1.38 min, 314.2 [M+1]⁺.

Example 47

To a mixture of Compound 48 (100 mg, 0.319 mmol), HATU (183 mg, 0.478mmol) and (2S,6R)-2,6-dlmethylpiperazine (73 mg, 0.638 mmol) in DMF (8mL) was added DIEA (0.2 mL) and stirred at 50° C. overnight. The mixturewas poured into water and filtered, washed with water, purified bypre-HPLC to give Compound 49 (38 mg, 29% yield) as yellow solid. LC-MS:Rt=1.207 min, 410.0 [M+1]⁺

Example 48

Compound 50 is prepared according to the procedure described in Example47: Yield=15%, 26 mg, yellow solid. LC-MS: 410.2 [M+1]⁺.

Example 49

To a solution of SM7 (17.2 g, 100 mmol) and Et₃N (27.7 ml, 200 mmol) inMeCN, ethyl carbonochloridate (14.2 ml, 150 mmol) was added drop wise at0° C. and stirred at r.t. overnight. The reaction mixture wasconcentrated and dissolved in EtOAc, washed with H₂O, brine, thenpurified by silica gel column (Petro ether: EtOAc=5:1) to give SM8 asyellow oil (12.6 g, 51.6% yield). LC-MS: 245.1 [M+1]⁺.

Example 50

To a solution of SM8 (3.48 mmol) in EtOH, 10% Pd/C (70 g) was added andstirred at r.t. for 2 h. The reaction mixture was filtered and thefiltrate was concentrated and dried under vacuum to give Compound SM9:Yield=89%, 480 mg, pale yellow oil. LC-MS: 155.3 [M+1]⁺.

Example 51

To a solution of Compound SM5 (595 mg, 3.1 mmol) and Compound SM9 (480mg, 3.1 mmol) in ethanol (8 mL) was added Et₃N (1.2 mL, 8.6 mmol) andthe mixture was stirred at reflux for 18 h. After cooling, the mixturewas concentrated and the residue was diluted with EtOAc to get Compound51 (430 mg, 47% yield) as brown solid. LC-MS: Rt=1.073 min, 292.0[M+1]⁺.

Example 52

Compound 52 is prepared according to the procedure described in Example41: Yield=58%, 40 mg, yellow solid. LC-MS: 333.9 [M+1]⁺.

Example 53

Compound 53 is prepared according to the procedure described in Example47: Yield=95%, 320 mg, yellow solid. LC-MS: 263.9 [M+1]⁺.

Example 54

Compound 54 is prepared according to the procedure described in Example47: Yield=13%, 18 mg, yellow solid. LC-MS: 360.0 [M+1]⁺.

Example 55

Compound 54 is prepared according to the procedure described in Example47: Yield=14%, 32 mg, yellow solid. LC-MS: 360.2 [M+1]⁺.

Example 56

The following compounds prepared according to the methods used for thepreparation of compounds 52 and 53.

Example 57 Representative Cell-Based IC₅₀ Data

Inhibitory activity on cell proliferation of representative compounds ofthe invention was determined using an Alamar Blue cell viability assayas described hereafter.

3000 cancer cells in 100 uL of cell culture media were plated in eachwell of a 96-well clear bottom, black wall cell culture-pretreatedplate.

The next day compounds are serially diluted (3-fold in cell culturemedia) across a 96-well polypropylene mother plate from row A to row F,to yield 6 concentrations (10 uM, 3.3 uM, 1.1 uM, 370 nM, 124 nM and 41nM) for each test compound. Rows G and H contain only DMSO.

Once titrations are made, the media in plates with cells were disposedand 100 μL of drug dilutions are transferred to plates with cells. Aftera ninety six-hour incubation at 37° C., 10 uL of resazurin solution fromAlamar Blue Cell Viability kit (Invitrogen, Carlsbad, Calif.) was addedto the media and cells were incubated at 37° C. for three more hours. Atthe end of this incubation the production of resofurin was measuredusing Spectrmax M2 microplate reader (Molecular Devices, Sunnyvale,Calif.)

Example 58 qRT-PCR Assay for Selective Inhibition of RNA Polymerase ITranscription

3000 cancer cells in 100 uL of cell culture media were plated in eachwell of a 96-well clear bottom, black wall cell culture-pretreatedplate.

The next day compounds are serially dilated (3-fold in cell culturemedia) across a 96-well polypropylene mother plate from row A to row F,to yield 6 concentrations (10 uM, 3.3 uM, 1.1 uM, 370 nM, 124 nM and 41nM) for each test compound. Rows G and H contain only DMSO.

Once titrations are made, the media in plates with cells were disposedand 100 μL of drug dilutions are transferred to plates with cells. Aftera ninety six-hour incubation at 37° C., 10 uL of resazurin solution fromAlamar Blue Cell Viability kit (Invitrogen, Carlsbad, Calif.) was addedto the media and cells were incubated at 37° C. for three more hours.

At the end of this incubation the production of resofarin was measuredusing Spectrmax M2 microplate reader (Molecular Devices, Sunnyvale,Calif.)

The Pol I transcription assay was used to measure thecormpound-dependent inhibition of the synthesis of rRNA versus mRNA.Briefly, this procedure utilizes a quantitative real time polymerasechain reaction assay (qRT-PCR) to quantify the amount of newlysynthesized rRNA and mRNA in cancer cells treated with the drugs. Theformat of this assay is the same for all cell lines tested. Assayprotocol is described hereafter.

2*10⁵ cancer cells in 2 mL of cell culture media were plated in eachwell of a 6-well clear bottom, black wall cell culture-pretreated plate.The next day compounds are serially diluted (5-fold in cell culturemedia) in 15 mL conical tubes to yield 6 concentrations (25 uM 5 uM, 1uM, 200 nM, 40 nM and 8 nM) for each test compound.

Once titrations are made, the media in plates with cells were disposedand 2 mL of drug dilutions are transferred to plates with cells. Aftertwo-hour incubation at 37° C., the media with drug dilutions isdisposed, the cells in the plate are washed once with 2 mL of ice-coldPBS and the total RNA from cells is isolated using RNAqueous®-MicroTotal RNA Isolation Kit (Lechnologies, Carlsbad, Calif.) according tothe manufacturer's protocol) and its concentration was determined usingRibogreen reagent (Life Lechnologies, Carlsbad, Calif.).

Relative levels of 45S pre-rRNA and c-myc mRNA were measured usingApplied Biosystems' (Foster City, Calif.) proprietary primers-probe setfor c-myc ruRNA and custom primers probe set (forward primer:CCGCGCTCTACCTTACCTACCT (SEQ ID 1), reverse primer:GCATGGCTTAATCTTTGAGACAAG (SEQ ID 2), probe: TTGATCCTGCCAGTAGC (SEQ ID3)) for pre-rRNA. Analysis was run on 7500HT Real Time PCR System(Applied Biosystems, Foster City, Calif.).

Example 59 Cell-Free Pol I Transcription Assay

To measure the direct effect of representative compounds on RNAPolymerase 1 transcription, a nuclear extract-based assay was used.Assay protocol is described hereafter.

Compounds are serially diluted (5-fold in cell culture media) across a96-well polypropylene mother plate from row A to row E, to yield 5concentrations (50 uM, 10 uM, 2 uM, 400 nM and 80 nM) for each testcompound. Row G contained only DMSO.

Once titrations were made, the reaction mixture consisting of 30 ng/uLDNA template corresponding to (−160/+379) region on rDNA and 3 mg/mLnuclear extract isolated from HeLa S3 cells in a buffer containing 10 mMTris HCl pH 8.0, 80 mM KCl, 0.8% polyvinyl alcohol, 10 mg/mL a-amanitinwas combined with the test compounds and incubated at ambient for 20min.

Transcription was initiated by addition of rNTP mix (New EnglandBiolabs, Ipswich, Mass.) to a final concentration of 1 mM and wasincubated for one hour at 30° C. Afterwards DNase I was added and thereaction was further incubated for 2 hr at 37° C.

DNase digestion was terminated by the addition of EDTA to finalconcentration of 10 mM, followed immediately by 10 min incubation at 75°C., and then samples were transferred to 4° C. The levels of resultanttranscript were analyzed by qRT-PCR on 7500HT Real Time PCR System(Applied Biosystems, Foster City, Calif.) using the followingprimer-probe set: Pol I probe ctctggcctaccggtgacccggcta, Pol I forwardprimer gctgacacgctgtcctctggcg and Pol I reverse primerggctcaagcaggagcgcggc.

Example 60 Testing Inhibition of RNA Polymerase I and II—DrivenTranscriptions

MM231 cells were plated in a 6-well format at 2*10̂5 cells/wellovernight. The next day the cells were treated by a dilution series (6doses total: 25 uM, 5 uM, 1 uM, 200 nM, 40 nM, 8 nM) of test compounds.Two hours after the beginning of treatment cells were washed and lysedfor RNA isolation that was performed using RNAqueous-Mini Total RNAisolation kit (Ambion).

The resulting RNA concentrations were determined using Quant-iTRiboGreen RNA Assay Kit (Molecular Probes). Effect on RNA Polymerase Iand RNA Polyrnerase II—driven transcription was assessed by monitoringresulting levels of 45S pre-rRNA and eMYC mRNA respectively. For this weperformed Taqman qRT-PCR assay using TaqMan® RNA-to-Ct™ 1-Step Kit (LifeTechnologies) with custom primer-probe set for 45S pre-rRNA (Drygin etall 2009 Cancer Res 69:7653) and Hs00153408_m1 primer-probe mix (LifeTechnologies) for eMYC mRNA. The assay was performed on AppliedBiosystems 7500 Fast Real-Time PCR System (ABI) using AbsoluteQuantitation method. The data was analyzed using GraphPad Prism(GraphPad) software.

Representative Pol I transcription inhibition, in MM231 cell line, fromquantitative PCR (QPCR) (Example 86 & Example 87) data is provided inTable 1.

TABLE 1 Compound ID 41 42 44 45 52 5 Pol I A B B A D D +++ indicates anactivity of less than 1 μM; ++ indicates an activity of greater than 1μM and less than 5 μM; + indicates an activity of greater than 5 μM andless than 10 μM; and − indicates an activity of greater than 10 μM.

Example 61 Anti-Cancer Activity of Representative Compounds

Representative cell proliferation inhibition from Alamar Blue assay,(e.g. Example 84 herein) is provided in Table 2.

TABLE 2 Cell Line Compound ID MDA-MB-231 SK-BR-3 12 B B 13 B B 15 B B 14B B 19 B B 20 B B 22 C B 21 D D 26 B B 27 B B 29 B B 28 B B 34 B B 36 BB 35 B B 62 D D 61 D D 60 D D 63 D D 58 B B 57 B B 56 D D A indicates anactivity of less than 1 μM; and B indicates an activity of greater than1 μM and less than 5 μM; C indicates an activity of greater than 5 μmand less than 10 μM; and D indicates an activity of greater than 10 μM.

Example 62 Anti-Cancer Activity of Representative Compounds

Representative cell proliferation inhibition from Alamar Blue assay(e.g. Example 84 herein) is provided in Table 3.

TABLE 3 Compound ID Cell line 5 52 55 39 41 SKM-1_1 B A P12- B BICHIKAWA THP-1 B B KG-1 B B NB-4-1 B B ML-2 B B MM231 D B SK-BR-3 D B AA indicates an activity of less than 1 μM; and B indicates an activityof greater than 1 μM and less than 5 μM; C indicates an activity ofgreater than 5 μm and less than 10 μM; and D indicates an activity ofgreater than 10 μM.

The above description of the disclosed embodiments is provided to enableany person skilled in the art to make or use the invention. Variousmodifications to these embodiments will be readily apparent to thoseskilled in the art, and the generic principles described herein can beapplied to other embodiments without departing from the spirit or scopeof the invention. Thus, it is to be understood that the description anddrawings presented herein represent a presently preferred embodiment ofthe invention and are therefore representative of the subject matterwhich is broadly contemplated by the present invention. It is furtherunderstood that the scope of the present invention fully encompassesother embodiments that may become obvious to those skilled in the artand that the scope of the present invention is accordingly not limited.

1.-22. (canceled)
 23. A compound having the structure of Formula I:

or a pharmaceutically acceptable salt, hydrate, or tautomer thereof;wherein: each Z₁, Z₂, Z₃, and Z₄ is N, CH, or CR₁, provided any three Nare non-adjacent; and further provided that one or more of Z₁, Z₂, Z₃,and Z₄ is CR₁; each R₁ is independently an optionally substituted C₁-C₈alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl,C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group, oreach R₁ is independently H, halo, CF₃, OR₂, NR₂R₃, NR₂OR₃, NR₂NR₂R₃,SR₂, SOR₂, SO₂R₂, SO₂NR₂R₃, NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃, NR₂COR₃, CN,COOR₂, COOH, CONR₂R₃, OOCR₂, COR₂, or NO₂; and wherein R₂ and R₃ groupson the same atom or on adjacent atoms can be linked to form a 3-8membered ring, optionally containing one or more N, O or S atoms; andeach R₂ and R₃ groups, and each ring formed by linking R₂ and R₃ groupstogether, is optionally substituted with one or more substituentsselected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′,SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂,OOCR′, COR′, and NO₂, wherein each R′ is independently H, C₁-C₆ alkyl,C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy,amino, and ═O; wherein two R′ can be linked to form a 3-7 membered ringoptionally containing up to three heteroatoms selected from N, O and S;or each R₁ is independently —W, -L-W, or —X-L-A; wherein X is NR₆, O, orS; W is an optionally substituted 4-7 membered azacyclic ring,optionally containing an additional heteroatom selected from N, O and Sas a ring member; L is a C₁-C₁₀ alkylene, C₁-C₁₀ heteroalkylene, C₂-C₁₀alkenylene or C₂-C₁₀ heteroalkenylene linker, each of which may beoptionally substituted with one or more substituents selected from thegroup consisting of halogen, oxo (═O), or C₁-C₆ alkyl; and A isheterocycloalkyl, heteroaryl or NR₄R₅ wherein, R₄ and R₅ areindependently H, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl,C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl,C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group; or R₄ and R₅ can be linkedto form a 3-8 membered ring, optionally containing one or more N, O orS; and each R₄ and R₅ groups, and each ring formed by linking R₄ and R₅groups together, is optionally substituted with one or more substituentsselected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′,SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂,OOCR′, COR′, and NO₂, wherein each R′ is independently H, C₁-C₆ alkyl,C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy,amino, and ═O; wherein two R′ can be linked to form a 3-7 membered ringoptionally containing up to three heteroatoms selected from N, O and S;R₆ is H, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group, or R₆ can be linked to R₄ orR₅ to form a 3-8 membered ring; and R₄ or R₅ is optionally substitutedwith one or more substituents selected from halo, ═O, ═N—CN, ═N—OR′,═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′,NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ isindependently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂heteroarylalkyl, each of which is optionally substituted with one ormore groups selected from halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O; wherein two R′ can belinked to form a 3-7 membered ring optionally containing up to threeheteroatoms selected from N, O and S; Y is an optionally substituted 5-6membered carbocyclic or heterocyclic ring; and X₁ is an optionallysubstituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl, C₂-C₈heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl, C₂-C₈heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂heteroarylalkyl group, optionally substituted with one or more halogens,═O, CF₃, CN, OR₇, NR₈R₉, SR₇, SO₂NR₈R₉, C₁-C₈ alkyl, C₂-C₈ heteroalkyl,C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl,C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group; wherein each R₇, R₈ and R₉is independently selected from H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of which is optionallysubstituted with one or more groups selected from halo, ═O, ═N—CN,═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂,NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂; whereineach R′ is independently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl,C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, orC₆-C₁₂ heteroarylalkyl, each of which is optionally substituted with oneor more groups selected from halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O; wherein two R′ can belinked to form a 3-7 membered ring optionally containing up to threeheteroatoms selected from N, O and S; or X₁ is MR₂R₃, SOR₂, SO₂R₂,SO₂NR₂R₃, NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃, NR₂COR₃, CN, COOR₂, COOH,CONR₂R₃, OOCR₂, COR₂, or NO₂.
 24. The compound of claim 23, having thestructure of Formula II(A), II(B), II(C), II(D), or II(E):

or a pharmaceutically acceptable salt, hydrate, or tautomer thereof;wherein: Z₁, Z₂, Z₃ and Z₄ are independently CH or CR₁; each R₁ isindependently an optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl,C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl,C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group, or each R₁ is independentlyhalo, CF₃, OR₂, NR₂R₃, NR₂OR₃, NR₂NR₂R₃, SR₂, SOR₂, SO₂R₂, SO₂NR₂R₃,NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃, NR₂COR₃, CN, COOR₂, COOH, CONR₂R₃,OOCR₂, COR₂, or NO₂; or each R₁ is independently —W, -L-W, or —X-L-A;wherein X is NR₆, O, or S; W is an optionally substituted 4-7 memberedazacyclic ring, optionally containing an additional heteroatom selectedfrom N, O and S as a ring member; L is a C₁-C₁₀ alkylene, C₁-C₁₀heteroalkylene, C₂-C₁₀ alkenylene or C₂-C₁₀ heteroalkenylene linker,each of which may be optionally substituted with one or moresubstituents selected from the group consisting of halogen, oxo (═O), orC₁-C₆ alkyl; and A is heterocycloalkyl, heteroaryl or NR₄R₅ wherein, R₄and R₅ are independently H, optionally substituted C₁-C₈ alkyl, C₂-C₈heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group; R₄ and R₅can be linked to form a 3-8 membered ring, optionally containing one ormore N, O or S; and each R₄ and R₅ groups, and each ring formed bylinking R₄ and R₅ groups together, is optionally substituted with one ormore substituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′,N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN,COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independentlyH, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S; R₆ is H, optionally substituted C₁-C₈ alkyl, C₂-C₈heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group; or R₆ canbe linked to R₄ or R₅ to form a 3-8 membered ring; and R₄ or R₅ isoptionally substituted with one or more substituents selected from halo,═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′,NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂,wherein each R′ is independently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl,C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of which is optionallysubstituted with one or more groups selected from halo, C₁-C₄ alkyl,C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O;wherein two R′ can be linked to form a 3-7 membered ring optionallycontaining up to three heteroatoms selected from N, O and S; Y is anoptionally substituted 5-6 membered carbocyclic or heterocyclic ring; X₁is an optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group, or X₁ is H, NR₂R₃, SOR₂,SO₂R₂, SO₂NR₂R₃, NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃, NR₂COR₃, CN, COOR₂,COOH, CONR₂R₃, OOCR₂, COR₂, or NO₂; wherein R₂ and R₃ groups on the sameatom or on adjacent atoms can be linked to form a 3-8 membered ring,optionally containing one or more N, O or S; and each R₂ and R₃ groups,and each ring formed by linking R₂ and R₃ groups together, is optionallysubstituted with one or more substituents selected from halo, ═O, ═N—CN,═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂,NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, whereineach R′ is independently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl,C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, orC₆-C₁₂ heteroarylalkyl, each of which is optionally substituted with oneor more groups selected from halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O; wherein two R′ can belinked to form a 3-7 membered ring optionally containing up to threeheteroatoms selected from N, O and S.
 25. The compound of claim 23,having the structure of Formula III(A), III(B) or III(C):

or a pharmaceutically acceptable salt, hydrate, or tautomer thereof;wherein: L is a C₁-C₁₀ alkylene, C₁-C₁₀ heteroalkylene, C₂-C₁₀alkenylene, or C₂-C₁₀ heteroalkenylene linker, each of which may beoptionally substituted with one or more substituents selected from thegroup consisting of halogen, oxo (═O), or C₁-C₆ alkyl; A isheterocycloalkyl, heteroaryl or NR₄R₅ wherein R₄ and R₅ areindependently H, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl,C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl,C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group; or R₄ and R₅ can be linkedto form a 3-8 membered ring, optionally containing one or more N, O orS; and each R₄ and R₅ groups, and each ring formed by linking R₄ and R₅groups together, is optionally substituted with one or more substituentsselected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′,SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂,OOCR′, COR′, and NO₂, wherein each R′ is independently H, C₁-C₆ alkyl,C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy,amino, and ═O; wherein two R′ can be linked to form a 3-7 membered ringoptionally containing up to three heteroatoms selected from N, O, and S;X is NR₆, O, or S; R₆ is H, optionally substituted C₁-C₈ alkyl, C₂-C₈heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group; or R₆ canbe linked to R₄ or R₅ to form a 3-8 membered ring; and R₄ or R₅ isoptionally substituted with one or more substituents selected from halo,═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′,NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂,wherein each R′ is independently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl,C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of which is optionallysubstituted with one or more groups selected from halo, C₁-C₄ alkyl,C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O;wherein two R′ can be linked to form a 3-7 membered ring optionallycontaining up to three heteroatoms selected from N, O, and S; X₁ is anoptionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl,C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C_(i)-C₈ acyl,C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, orC₆-C₁₂ heteroarylalkyl group, or X₁ is H, NR₂R₃, SOR₂, SO₂R₂, SO₂NR₂R₃,NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃, NR₂COR₃, CN, COOR₂, COOH, CONR₂R₃,OOCR₂, COR₂, or NO₂; wherein R₂ and R₃ groups on the same atom or onadjacent atoms can be linked to form a 3-8 membered ring, optionallycontaining one or more N, O or S; and each R₂ and R₃ groups, and eachring formed by linking R₂ and R₃ groups together, is optionallysubstituted with one or more substituents selected from halo, ═O, ═N—CN,═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂,NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, whereineach R′ is independently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl,C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, orC₆-C₁₂ heteroarylalkyl, each of which is optionally substituted with oneor more groups selected from halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O; wherein two R′ can belinked to form a 3-7 membered ring optionally containing up to threeheteroatoms selected from N, O, and S; and (U)_(n) and (U)_(m) are eachindependently H, halogen, CF₃, CN, OR₇, NR₈R₉, SR₇, SO₂NR₈R₉, C₁-C₁₀alkyl, C₁-C₁₀ heteroalkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀ heteroalkenyl, eachof which may be optionally substituted with one or more halogens, ═O, oran optionally substituted 3-7 membered carbocyclic or heterocyclic ring;wherein each R₇, R₈ and R₉ is independently selected from H, C₁-C₆alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl,C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each ofwhich is optionally substituted with one or more groups selected fromhalo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂,NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′,COR′, and NO₂; wherein each R′ is independently H, C₁-C₆ alkyl, C₂-C₆heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy,amino, and ═O; wherein two R′ can be linked to form a 3-7 membered ringoptionally containing up to three heteroatoms selected from N, O, and S.26. The compound of claim 23, or a pharmaceutically acceptable salt,hydrate, or tautomer thereof, wherein: L is a C₁-C₁₀ alkylene, C₁-C₁₀heteroalkylene, C₂-C₁₀ alkenylene or C₂-C₁₀ heteroalkenylene linker,each of which is optionally substituted with one or more substituentsselected from the group consisting of halogen, oxo (═O), and C₁-C₆alkyl; A is heterocycloalkyl, heteroaryl, or NR₄R₅, wherein R₄ and R₅are independently H, optionally substituted C₁-C₈ alkyl, C₂-C₈heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group; R₄ and R₅can be linked to form a 3-8 membered ring, optionally containing one ormore N, O or S; and each R₄ and R₅ groups, and each ring formed bylinking R₄ and R₅ groups together, is optionally substituted with one ormore substituents selected from halo, ═O, ═N—CN, ═NOR′, ═NR′, OR′,N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN,COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independentlyH, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O, and S; X is NR₆, O, or S; R₆ is H, optionally substitutedC₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl,C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀aryl, C5-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkylgroup; or R₆ can be linked to R₄ or R₅ to form a 3-8 membered ring; andR₄ or R₅ are optionally substituted with one or more substituentsselected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′,SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂,OOCR′, COR′, and NO₂; X₂ is H, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₂-C₁₀alkenyl, or C₂-C₁₀ heteroalkenyl, each of which is optionallysubstituted with one or more halogens, ═O, or an optionally substituted3-7 membered carbocyclic or heterocyclic ring; (U)_(n) and (U)_(m) areeach independently H, halogen, CF₃, CN, OR₇, NR₈R₉, SR₇, SO₂NR₈R₉,C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀heteroalkenyl, each of which is optionally substituted with one or morehalogens, ═O, or an optionally substituted 3-7 membered carbocyclic orheterocyclic ring, wherein each R₇, R₈ and R₉ is independently selectedfrom H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl,C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂heteroarylalkyl, each of which is optionally substituted with one ormore groups selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂; and wherein R₂ and R₃ groups on the sameatom or on adjacent atoms are linked to form a 3-8 membered ring,optionally containing one or more N, O, or S; and each R₂ and R₃ groups,and each ring formed by linking R₂ and R₃ groups together, is optionallysubstituted with one or more substituents selected from halo, ═O, ═N—CN,═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂,NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂.
 27. Thecompound of claim 23, of a pharmaceutically acceptable salt, hydrate, ortautomer thereof, wherein X₂ is H.
 28. A compound having the structureof Formula III(A)(1), III(B)(1), III(C)(1), V(A), V(B), or V(C):

or a pharmaceutically acceptable salt, hydrate, or tautomer thereof,wherein: L is a bond, C₁-C₁₀ alkylene, C₁-C₁₀ heteroalkylene, C₂-C₁₀alkenylene, or C₂-C₁₀ heteroalkenylene linker, each of which may beoptionally substituted with one or more substituents selected from thegroup consisting of halogen, oxo (═O), and C₁-C₆ alkyl; A isheterocycloalkyl, heteroaryl, or NR₄R₅ wherein, R₄ and R₅ areindependently H, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl,C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl,C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group; or R₄ and R₅ can be linkedto form a 3-8 membered ring, optionally containing one or more N, O orS; and each R₄ and R₅ groups, and each ring formed by linking R₄ and R₅groups together, is optionally substituted with one or more substituentsselected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′,SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂,OOCR′, COR′, and NO₂, wherein each R′ is independently H, C₁-C₆ alkyl,C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy,amino, and ═O; wherein two R′ can be linked to form a 3-7 membered ringoptionally containing up to three heteroatoms selected from N, O and S;X is NR₆, O, or S; R₆ is H, optionally substituted C₁-C₈ alkyl, C₂-C₈heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group; or R₆ canbe linked to R₄ or R₅ to form a 3-8 membered ring; and R₄ or R₅ isoptionally substituted with one or more substituents selected from halo,═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′,NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂,wherein each R′ is independently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl,C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of which is optionallysubstituted with one or more groups selected from halo, C₁-C₄ alkyl,C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O;wherein two R′ can be linked to form a 3-7 membered ring optionallycontaining up to three heteroatoms selected from N, O and S; X₂ ishydrogen, or an optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl,C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl,C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group; or X₂ is H, C₁-C₁₀ alkyl,C₁-C₁₀ heteroalkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀ heteroalkenyl, each ofwhich is optionally substituted with one or more halogens, ═O, or anoptionally substituted 3-7 membered carbocyclic or heterocyclic ring;and (U)_(n) and (U)_(m) are each independently H, halogen, CF₃, CN, OR₇,NR₈R₉, SR₇, SO₂NR₈R₉, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₂-C₁₀ alkenyl,or C₂-C₁₀ heteroalkenyl, each of which may be optionally substitutedwith one or more halogens, ═O, or an optionally substituted 3-7 memberedcarbocyclic or heterocyclic ring; wherein each R₇, R₈ and R₉ isindependently selected from H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of which is optionallysubstituted with one or more groups selected from halo, ═O, ═N—CN,═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂,NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂.
 29. Acompound having the structure of Formula IV(A), IV(B), VI(A), VI(B), orVI(C):

or a pharmaceutically acceptable salt, hydrate, or tautomer thereof;wherein: B₁ is a bond or C═O; B₂ is X-L-A; L is a C₁-C₁₀ alkylene,C₁-C₁₀ heteroalkylene, C₂-C₁₀ alkenylene, or C₂-C₁₀ heteroalkenylenelinker, each of which may be optionally substituted with one or moresubstituents selected from the group consisting of halogen, oxo (═O),and C₁-C₆ alkyl; A is heterocycloalkyl, heteroaryl, or NR₄R₅ wherein R₄and R₅ are independently H, optionally substituted C₁-C₈ alkyl, C₂-C₈heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group, or R₄ andR₅ can be linked to form a 3-8 membered ring, optionally containing oneor more N, O or S; and each R₄ and R₅ groups, and each ring formed bylinking R₄ and R₅ groups together, is optionally substituted with one ormore substituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′,N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN,COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independentlyH, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S; X is CR₆R₆, NR₆, O, or S; wherein R₆ is H, optionallysubstituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl, C₂-C₈heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl, C₂-C₈heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂heteroarylalkyl group; or R₆ can be linked to R₄ or R₅ to form a 3-8membered ring; and (U)_(n) and (U)_(m) are each independently H,halogen, CF₃, CN, OR₇, NR₈R₉, SR₇, SO₂NR₈R₉, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀ heteroalkenyl, each of which maybe optionally substituted with one or more halogens, ═O, or anoptionally substituted 3-7 membered carbocyclic or heterocyclic ring;wherein each R₇, R₈ and R₉ is independently selected from H, C₁-C₆alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl,C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each ofwhich is optionally substituted with one or more groups selected fromhalo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂,NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′,COR′, and NO₂; wherein each R′ is independently H, C₁-C₆ alkyl, C₂-C₆heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, or C₁-C₆ heteroacyl.
 30. Acompound having the structure of Formula VII:

or a pharmaceutically acceptable salt, hydrate, or tautomer thereof;wherein: B is an optionally substituted 5-6 membered carbocyclic orheterocyclic ring; Z₅ is N or CX₂; each Z₁ and Z₄ is N, CH, or CR₁; eachR₁ is independently an optionally substituted C₁-C₈ alkyl, C₂-C₈heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈heteroalkynyl, C ₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group, or eachR₁ is independently H, halo, CF₃, OR₂, NR₂R₃, NR₂OR₃, NR₂NR₂R₃, SR₂,SOR₂, SO₂R₂, SO₂NR₂R₃, NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃, NR₂COR₃, CN,COOR₂, COOH, CONR₂R₃, OOCR₂, COR₂, or NO₂; wherein R₂ and R₃ groups onthe same atom or on adjacent atoms can be linked to form a 3-8 memberedring, optionally containing one or more N, O or S atoms; and each R₂ andR₃ groups, and each ring formed by linking R₂ and R₃ groups together, isoptionally substituted with one or more substituents selected from halo,═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′,NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂,wherein each R′ is independently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl,C₁-C₆ acyl, C₂₋C₆ heteroacyl, C₆-C₁₀ aryl, C₅₋C₁₀ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of which is optionallysubstituted with one or more groups selected from halo, C₁-C₄ alkyl,C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁₋C₆ heteroacyl, hydroxy, amino, and ═O;wherein two R′ can be linked to form a 3-7 membered ring optionallycontaining up to three heteroatoms selected from N, O, and S; two R₁groups on adjacent atoms may form a carboxylic ring, heterocyclic ring,aryl or heteroaryl, each of which may be optionally substituted and/orfused with a cyclic ring; or each R₁ is independently —W, -L-W, or—X-L-A; wherein X is NR₆, O, or S; W is an optionally substituted 4-7membered azacyclic ring, optionally containing an additional heteroatomselected from N, O, and S as a ring member; L is a C₁-C₁₀ alkylene,C₁-C₁₀ heteroalkylene, C₂-C₁₀ alkenylene, or C₂-C₁₀ heteroalkenylenelinker, each of which may be optionally substituted with one or moresubstituents selected from the group consisting of halogen, oxo (═O), orC₁-C₆ alkyl; and A is heterocycloalkyl, heteroaryl, or NR₄R₅, wherein R₄and R₅ are independently H, optionally substituted C₁-C₈ alkyl, C₂-C₈heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group; or R₄ andR₅ can be linked to form a 3-8 membered ring, optionally containing oneor more N, O, or S; and each R₄ and R₅ groups, and each ring formed bylinking R₄ and R₅ groups together, is optionally substituted with one ormore substituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′,N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN,COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independentlyH, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O, and S; R₆ is H, optionally substituted C₁-C₈ alkyl, C₂-C₈heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group; or R₆ canbe linked to R₄ or R₅ to form a 3-8 membered ring; and R₄ or R₅ isoptionally substituted with one or more substituents selected from halo,═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′,NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂,wherein each R′ is independently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl,C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of which is optionallysubstituted with one or more groups selected from halo, C₁-C₄ alkyl,C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O;wherein two R′ can be linked to form a 3-7 membered ring optionallycontaining up to three heteroatoms selected from N, O, and S; X₁ is anoptionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl,C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl,C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, orC₆-C₁₂ heteroarylalkyl group, each of which is optionally substitutedwith one or more halogens, ═O, CF₃, CN, OR₇, NR₈R₉, SR₇, SO₂NR₈R₉, C₁-C₈alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl,C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group; orX₁ is NR₂R₃, SOR₂, SO₂R₂, SO₂NR₂R₃, NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃,NR₂COR₃, CN, COOR₂, COOH, CONR₂R₃, OOCR₂, COR₂, or NO₂; X₂ is, H,halogen, CF₃, CN, OR₇, NR₈R₉, SR₇, SO₂NR₈R₉, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀ heteroalkenyl, each of which maybe optionally substituted with one or more halogens, ═O, or anoptionally substituted 3-7 membered carbocyclic or heterocyclic ring;wherein each R₇, R₈ and R₉ is independently selected from H, C₁-C₆alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl,C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each ofwhich is optionally substituted with one or more groups selected fromhalo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂,NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′,COR′, and NO₂, wherein each R′ is independently H, C₁-C₆ alkyl, C₂-C₆heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, and C₁-C₆ heteroacyl; eachX₃, X₄ and X₅ is N or CR₁₀; each R₁₀ is independently an optionallysubstituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl, C₂-C₈heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl, C₂-C₈heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂heteroarylalkyl group, or each R₁₀ is independently H, halo, CF₃, OR₂,NR₂R₃, NR₂OR₃, NR₂NR₂R₃, SR₂, SOR₂, SO₂R₂, SO₂NR₂R₃, NR₂SO₂R₃,NR₂CONR₂R₃, NR₂COOR₃, NR₂COR₃, CN, COOR₂, COOH, CONR₂R₃, OOCR₂, COR₂, orNO₂; wherein R₂ and R₃ groups on the same atom or on adjacent atoms canbe linked to form a 3-8 membered ring, optionally containing one or moreN, O or S atoms; and each R₂ and R₃ groups, and each ring formed bylinking R₂ and R₃ groups together, is optionally substituted with one ormore substituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′,N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN,COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independentlyH, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁₋C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-_(C10) heteroaryl, C₇₋C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C ₁₋C₆ acyl, C₁-C₆heteroacyl, hydroxy, amino, and ═O; wherein two R′ can be linked to forma 3-7 membered ring optionally containing up to three heteroatomsselected from N, O, and S; two R₁₀ groups on adjacent atoms may form acarboxylic ring, heterocyclic ring, aryl or heteroaryl, each of whichmay be optionally substituted and/or fused with a cyclic ring; or eachR₁₀ is independently —W, -L-W, or —X-L-A.
 31. The compound of claim 30,having the structure of Formula VIII:

or a pharmaceutically acceptable salt, hydrate, or tautomer thereof;wherein: Z₁ and Z₄ are each independently N, CH, or CR₁; wherein each R₁is independently an optionally substituted C₁-C₈ alkyl, C₂-C₈heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group, or eachR₁ is independently H, halo, CF₃, OR₂, NR₂R₃, NR₂OR₃, NR₂NR₂R₃, SR₂,SOR₂, SO₂R₂, SO₂NR₂R₃, NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃, NR₂COR₃, CN,COOR₂, COOH, CONR₂R₃, OOCR₂, COR₂, or NO₂; wherein R₂ and R₃ groups onthe same atom or on adjacent atoms can be linked to form a 3-8 memberedring, optionally containing one or more N, O or S atoms; and each R₂ andR₃ groups, and each ring formed by linking R₂ and R₃ groups together, isoptionally substituted with one or more substituents selected from halo,═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′,NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂,wherein each R′ is independently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl,C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of which is optionallysubstituted with one or more groups selected from halo, C₁-C₄ alkyl,C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O;wherein two R′ can be linked to form a 3-7 membered ring optionallycontaining up to three heteroatoms selected from N, O and S; or each R₁is independently —W, -L-W, or —X-L-A; wherein X is NR₆, O, or S; W is anoptionally substituted 4-7 membered azacyclic ring, optionallycontaining an additional heteroatom selected from N, O and S as a ringmember; L is a C₁-C₁₀ alkylene, C₁-C₁₀ heteroalkylene, C₂-C₁₀alkenylene, or C₂-C₁₀ heteroalkenylene linker, each of which may beoptionally substituted with one or more substituents selected from thegroup consisting of halogen, oxo (═O), and C₁-C₆ alkyl; and A isheterocycloalkyl, heteroaryl, or NR₄R₅ wherein, R₄ and R₅ areindependently H, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl,C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl,C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group; or R₄ and R₅ can be linkedto form a 3-8 membered ring, optionally containing one or more N, O orS; and each R₄ and R₅ groups, and each ring formed by linking R₄ and R₅groups together, is optionally substituted with one or more substituentsselected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′,SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂,OOCR′, COR′, and NO₂, wherein each R′ is independently H, C₁-C₆ alkyl,C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy,amino, and ═O; wherein two R′ can be linked to form a 3-7 membered ringoptionally containing up to three heteroatoms selected from N, O and S;R₆ is H, optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group; or R₆ can be linked to R₄ orR₅ to form a 3-8 membered ring; and R₄ or R₅ is optionally substitutedwith one or more substituents selected from halo, ═O, ═N—CN, ═N—OR′,═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′,NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ isindependently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂heteroarylalkyl, each of which is optionally substituted with one ormore groups selected from halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O; wherein two R′ can belinked to form a 3-7 membered ring optionally containing up to threeheteroatoms selected from N, O, and S; X₁ is an optionally substitutedC₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl,C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkylgroup, each of which is optionally substituted with one or morehalogens, ═O, CF₃, CN, OR₇, NR₈R₉, SR₇, SO₂NR₈R₉, C₁-C₈ alkyl, C₂-C₈heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group; or X₁ isNR₂R₃, SOR₂, SO₂R₂, SO₂NR₂R₃, NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃, NR₂COR₃,CN, COOR₂, COOH, CONR₂R₃, OOCR₂, COR₂, or NO₂; X₂ is, H, halogen, CF₃,CN, OR₇, NR₈R₉, SR₇, SO₂NR₈R₉, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₂-C₁₀alkenyl, or C₂-C₁₀ heteroalkenyl, each of which may be optionallysubstituted with one or more halogens, ═O, or an optionally substituted3-7 membered carbocyclic or heterocyclic ring; wherein each R₇, R₈ andR₉ is independently selected from H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl,C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of which is optionallysubstituted with one or more groups selected from halo, ═O, ═N—CN,═N—OR′, —NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂,NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂; whereineach R′ is independently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl,C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, orC₆-C₁₂ heteroarylalkyl, each of which is optionally substituted with oneor more groups selected from halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆acyl, C₁-C₆ heteroacyl; each X₃, X₄ and X₅ is N or CR₁₀; each R₁₀ isindependently an optionally substituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl,C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl,C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl group, or each R₁₀ is independentlyH, halo, CF₃, OR₂, NR₂R₃, NR₂OR₃, NR₂NR₂R₃, SR₂, SOR₂, SO₂R₂, SO₂NR₂R₃,NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃, NR₂COR₃, CN, COOR₂, COOH, CONR₂R₃,OOCR₂, COR₂, or NO₂; wherein R₂ and R₃ groups on the same atom or onadjacent atoms can be linked to form a 3-8 membered ring, optionallycontaining one or more N, O or S atoms; and each R₂ and R₃ groups, andeach ring formed by linking R₂ and R₃ groups together, is optionallysubstituted with one or more substituents selected from halo, ═O, ═N—CN,═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂,NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, whereineach R′ is independently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl,C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, orC₆-C₁₂ heteroarylalkyl, each of which is optionally substituted with oneor more groups selected from halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O; wherein two R′ can belinked to form a 3-7 membered ring optionally containing up to threeheteroatoms selected from N, O, and S; two R₁₀ groups on adjacent atomsmay form a carboxylic ring, heterocyclic ring, aryl or heteroaryl, eachof which may be optionally substituted and/or fused with a cyclic ring;or each R₁₀ is independently —W, -L-W, or —X-L-A; and (U)_(n) is H,halogen, CF₃, CN, OR₇, NR₈R₉, SR₇, SO₂NR₈R₉, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀ heteroalkenyl, each of which maybe optionally substituted with one or more halogens, ═O, or anoptionally substituted 3-7 membered carbocyclic or heterocyclic ring.32. A compound having the structure of Formula XIV(A), XIV(B), XIV(C),or XIV(D):

or a pharmaceutically acceptable salt, hydrate, or tautomer thereof;wherein: B₁ is a bond or C═O and B₂ is X-L-A; L is a C₁-C₁₀ alkylene,C₁-C₁₀ heteroalkylene, C₂-C₁₀ alkenylene, or C₂-C₁₀ heteroalkenylenelinker, each of which may be optionally substituted with one or moresubstituents selected from the group consisting of halogen, oxo (═O),and C₁-C₆ alkyl; A is heterocycloalkyl, heteroaryl, or NR₄R₅ wherein R₄and R₅ are independently H, optionally substituted C₁-C₈ alkyl, C₂-C₈heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group, or R₄ andR₅ can be linked to form a 3-8 membered ring, optionally containing oneor more N, O, or S; and each R₄ and R₅ groups, and each ring formed bylinking R₄ and R₅ groups together, is optionally substituted with one ormore substituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′,N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN,COOR′, CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independentlyH, C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S; X is CR₆R₆, NR₆, O, or S; wherein R₆ is H, optionallysubstituted C₁-C₈ alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl, C₂-C₈heteroalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl, C₂-C₈heteroacyl, C₆-C₁₀ aryl, C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂heteroarylalkyl group; or R₆ can be linked to R₄ or R₅ to form a 3-8membered ring; X₂ is H, halogen, CF₃, CN, OR₇, NR₈R₉, SR₇, SO₂NR₈R₉,C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀heteroalkenyl, each of which may be optionally substituted with one ormore halogens, ═O, or an optionally substituted 3-7 membered carbocyclicor heterocyclic ring; (U)_(n) and (U)_(m) are each independently H,halogen, CF₃, CN, OR₇, NR₈R₉, SR₇, SO₂NR₈R₉, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀ heteroalkenyl, each of which maybe optionally substituted with one or more halogens, ═O, or anoptionally substituted 3-7 membered carbocyclic or heterocyclic ring;wherein each R₇, R₈ and R₉ is independently selected from H, C ₁-C₆alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl,C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each ofwhich is optionally substituted with one or more groups selected fromhalo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂,NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′,COR′, and NO₂; wherein each R′ is independently H, C₁-C₆ alkyl, C₂-C₆heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl; each X₃ isN or CR₁₀; each R₁₀ is independently an optionally substituted C₁-C₈alkyl, C₂-C₈ heteroalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈alkynyl, C₂-C₈ heteroalkynyl, C₁-C₈ acyl, C₂-C₈ heteroacyl, C₆-C₁₀ aryl,C₅-C₁₂ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl group, oreach R₁₀ is independently H, halo, CF₃, OR₂, NR₂R₃, NR₂OR₃, NR₂NR₂R₃,SR₂, SOR₂, SO₂R₂, SO₂NR₂R₃, NR₂SO₂R₃, NR₂CONR₂R₃, NR₂COOR₃, NR₂COR₃, CN,COOR₂, COOH, CONR₂R₃, OOCR₂, COR₂, or NO₂; wherein R₂ and R₃ groups onthe same atom or on adjacent atoms can be linked to form a 3-8 memberedring, optionally containing one or more N, O, or S atoms; and each R₂and R₃ groups, and each ring formed by linking R₂ and R₃ groupstogether, is optionally substituted with one or more substituentsselected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′,SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂,OOCR′, COR′, and NO₂, wherein each R′ is independently H, C₁-C₆ alkyl,C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy,amino, and ═O; wherein two R′ can be linked to form a 3-7 membered ringoptionally containing up to three heteroatoms selected from N, O, and S;two R₁₀ groups on adjacent atoms may form a carboxylic ring,heterocyclic ring, aryl or heteroaryl, each of which may be optionallysubstituted and/or fused with a cyclic ring; or each R₁₀ isindependently —W, -L-W, or —X-L-A.
 33. The compound of claim 23, whereinthe compound has one of the following structures:

or a pharmaceutically acceptable salt, hydrate, or tautomer thereof. 34.The compound of claim 23, wherein the compound has one of the followingstructures:

or a pharmaceutically acceptable salt, hydrate, or tautomer thereof. 35.The compound of claim 28, wherein the compound has one of the followingstructures:

or a pharmaceutically acceptable salt, hydrate, or tautomer thereof. 36.The compound of claim 28, wherein the compound has one of the followingstructures:

or a pharmaceutically acceptable salt, hydrate, or tautomer thereof. 37.The compound of claim 30, wherein the compound has one of the followingstructures:

or a pharmaceutically acceptable salt, hydrate, or tautomer thererof.38. A method for treating cancer in a subject comprising administering acompound of claim 23, or a pharmaceutically acceptable salt, hydrate, ortautomer thereof.
 39. The method of claim 38, wherein the cancer is ofthe breast, lung, colorectum, liver, pancreas, lymph node, colon,prostate, brain, head and neck, skin, kidney, blood or heart.